@article {pmid42142451,
year = {2026},
author = {Razavi, A and Hou, J and Lin, SJ and Zhang, C and Kremen, WS and Fennema-Notestine, C and Elman, J and Holmans, P and Faraone, SV and Gaiteri, C and Hess, JL and Glatt, SJ},
title = {Predicted brain-regional gene expression patterns in individuals living with Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {29-40},
doi = {10.1016/j.neurobiolaging.2026.04.006},
pmid = {42142451},
issn = {1558-1497},
abstract = {Studying brain gene expression in Alzheimer's Disease (AD) remains difficult as postmortem brain is difficult to access, cannot be used to guide donor treatment, may be confounded by environmental factors before and after death, and is difficult to link to early AD states or disease progression. To circumvent these limitations, several studies have tested blood transcriptome biomarkers for AD. However, gene-expression levels in the blood have limited correlation with those in the brain. To evaluate the potential of monitoring Alzheimer's progression with peripheral data, we used transcriptome-imputation to identify brain-region-specific AD-associated gene-expression differences in cohorts with blood-based transcriptome data. This approach provides a high-resolution image of AD-associated molecular differences in the brains of individuals actively living with disease. We analyzed eight AD studies (777 AD cases, 779 cognitively unimpaired controls), imputing transcriptomes in 10 brain regions via the Brain Gene Expression and Network Imputation Engine (BrainGENIE). Hundreds of differentially expressed genes (DEGs) associated with AD were identified in nine brain regions, with anterior cingulate cortex and amygdala showing the most differential expression. AD-associated genes were enriched in pathways such as proteostasis, mitochondrial dysfunction, and immune activation. We observed significant yet moderate concordance between imputed AD-associated changes and those directly measured in the dorsolateral prefrontal cortex and cerebellum. These transcriptomic changes can guide future in vitro studies focused on pathogenesis or be targets of novel therapeutic development. In conclusion, we demonstrated the scope and utility of brain expression imputation from the peripheral transcriptome, laying the groundwork for biomarker discovery and prospective AD studies.},
}

@article {pmid42142620,
year = {2026},
author = {Shang, X and Chen, SY and Zhang, XY and Regina, I and Zhang, T and Luo, J and Yan, YZ and Qiao-yuanYao, and Tong, F and Pan, LH},
title = {Insulin in brain: The physiological functions and therapeutic insights for neurodegenerative diseases.},
journal = {Life sciences},
volume = {398},
number = {},
pages = {124468},
doi = {10.1016/j.lfs.2026.124468},
pmid = {42142620},
issn = {1879-0631},
abstract = {This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail. We emphasize the essential roles of insulin in the maintenance of cerebral glucose homeostasis, modulation of cognitive performance, regulation of appetite, promotion of cerebrovascular angiogenesis, and exertion of neuroprotective effects. We demonstrate how insulin resistance exacerbates characteristic neuropathological features in Alzheimer's disease (AD) and Parkinson's disease (PD), while insulin-based interventions ameliorate these pathologies through multiple mechanisms including increasing the activity of insulin-degrading enzyme, suppressing Aβ neurotoxicity, and reducing α-synuclein deposition. The review also systematically examines the neuroprotective effects of insulin sensitizers and their potential to reduce the risk of AD, while noting the complexity of their bidirectional regulatory role in PD, which warrants further investigation. Notably, intranasal insulin administration emerges as a promising non-invasive therapeutic approach that bypasses the blood-brain barrier via olfactory and trigeminal pathways, suggesting significant potential for cognitive enhancement and neuropathological mitigation. Nonetheless, it must be noted that the optimal dosage, long-term safety, and sustained efficacy of insulin therapy remain unclear, and the current evidence is derived primarily from preclinical studies or small-scale clinical trials. In summary, this review paper underscores the critical physiological roles of insulin in the brain and outlines novel therapeutic strategies for using insulin in the treatment of AD and PD.},
}

@article {pmid42142765,
year = {2026},
author = {Feng, Y and Zhang, C and Wei, Y and Liu, E and Sun, H and Flatt, P and Gault, V and Irwin, N and Hölscher, C and Hao, L and Zhang, Z},
title = {A novel bifunctional peptide predicted to target neuropeptide Y4 and GLP-1 receptors alleviates cognitive deficits in 5 × FAD mice by modulating cGAS-STING-mediated neuroinflammation.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118074},
doi = {10.1016/j.bcp.2026.118074},
pmid = {42142765},
issn = {1873-2968},
abstract = {Effective disease-modifying therapies for Alzheimer's disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo, NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden (P < 0.05), alleviated neuronal injury (P < 0.01), improved synaptic integrity (P < 0.01), and attenuated mitochondrial abnormalities (P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) (P < 0.05), cGAS (P < 0.05), STING (P < 0.05), and phosphorylated IRF3 (P < 0.01), together with decreased IL-1β (P < 0.05) and increased IL-10 (P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling (P < 0.05) and inflammatory responses (P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.},
}

@article {pmid42143322,
year = {2026},
author = {Gröbner, LS and Pietrzik, CU},
title = {Transport pathways across the blood-brain barrier for waste clearance and drug delivery.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00812-7},
pmid = {42143322},
issn = {2045-8118},
abstract = {The blood-brain barrier (BBB) displays a highly organized and complex structure, which is important for maintaining brain homeostasis and protecting the brain from foreign molecules or pathogens. Receptor-mediated transcytosis (RMT) is one of the main delivery pathways across the BBB for molecules that cannot pass the barrier via, e.g. paracellular diffusion. For understanding the treatment options in neurodegenerative diseases such as Alzheimer´s disease (AD), it is important to investigate transport pathways and mechanisms at the BBB for a potential delivery of drugs, antibodies or other compounds across the BBB. This review provides an overview of the different transport variants across the BBB and how they can be targeted in order to promote internalization or secretion into or out of the brain. Therefore, we want to focus on two characterized proteins: the low-density lipoprotein receptor-related protein 1 (LRP1), which is a key mediator of amyloid β (Aβ) clearance from the brain during AD, and transferrin receptor 1 (TfR1), which is already used as a target for antibody-delivery into the brain. Additionally, this review discusses two other important proteins, which have been less frequently addressed in research regarding transport mechanisms: P-glycoprotein (P-gp) as another transporter at the BBB and proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol homeostasis which promotes the degradation of the low-density lipoprotein receptor (LDLR) and LRP1. For these four main proteins, we aim to highlight existing approaches for targeting or inhibiting the aforementioned receptors or proteins. The approaches enable a higher penetration of the BBB, a better distribution in the brain, and ultimately fewer side effects of antibodies or nanoparticles. Here, we include lecanemab, trontinemab, dual TfR/CD98hc shuttles, evolocumab and alirocumab, immunoliposomes and other nanoparticles targeting TfR1 or LRP1. We will further highlight approaches which differ from these common ideas and demonstrate the current state of the art regarding drug delivery and waste clearance across the BBB.},
}

@article {pmid42144109,
year = {2026},
author = {Loukil, I and Vachon, A and Çaku, A and Plourde, M},
title = {Krill oil increase plasma omega-3 fatty acids more than fish oil in healthy adults: a double blind randomized controlled trial.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101346},
doi = {10.1016/j.ajcnut.2026.101346},
pmid = {42144109},
issn = {1938-3207},
abstract = {BACKGROUND: Omega-3 fatty acids (ω-3 FAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are recognized for their health benefits. However, their circulating levels after supplementation may be modulated by several factors, including sex, carriage of the apolipoprotein E4 allele (APOE4), and the chemical form of the supplement. Krill-oil delivers ω-3 FAs primarily as phospholipids (PL), whereas fish oil provides them as triglycerides (TG).

OBJECTIVE: To compare EPA and DHA concentrations after a supplementation with krill oil and fish oil and assess whether sex and APOE4 genotype modifies responses to supplementation.

METHODS: This double-blind, randomized clinical trial included 72 healthy adults (53 females, 19 males) matched for age and body mass index (BMI). Participants received 1.1 g/day ω-3 FAs through either krill oil (n=36) or fish oil (n=36) for 12 weeks. Plasma fatty acids were measured at baseline and at weeks 1, 2, 4, and 12 by gas chromatography-flame ionization detection. Differences in plasma ω-3 FAs concentrations by treatment, sex and APOE4 status, were analyzed.

RESULTS: Time-by-treatment interactions were significant for plasma delta over baseline concentrations of EPA (p = 0.0001) and DHA (p = 0.005), with krill oil resulting in ∼ 1.5-fold higher ΔEPA and ΔDHA compared to fish oil. The time-by-sex interaction was significant only for EPA (p = 0.026), with females having 1.5-fold greater increase than males at 12 weeks. Following supplementation with either krill oil or fish oil, APOE4 carriers had 3-fold and 1.6-fold higher EPA and DHA respectively, compared to baseline; however, these increases were not significantly different from those found in non-carriers.

CONCLUSIONS: Krill oil increased plasma ω-3 FAs more than fish oil, regardless of APOE4 genotype. Individuals with higher ω-3 FA requirements may achieve adequate enrichment with lower doses of krill oil compared to fish oil supplementation.

REGISTRATION NUMBER: NCT04279743. In https://clinicaltrials.gov.},
}

@article {pmid42144687,
year = {2026},
author = {Zhao, Q and Yu, Y and Wang, F and Wang, Y and Shao, P and Zhao, L},
title = {TARDBP Mediates the MAP3K11/SLC3A2/GPX4 Axis in Alzheimer's Disease Rats by Enhancing KRAS mRNA Stability.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {10},
pages = {e71181},
doi = {10.1111/jcmm.71181},
pmid = {42144687},
issn = {1582-4934},
support = {HAB202113//Huai'an Natural Science Research Program/ ; },
mesh = {Animals ; Rats ; *Alzheimer Disease/metabolism/genetics/pathology ; PC12 Cells ; *RNA Stability/genetics ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; *Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Male ; Hippocampus/metabolism/pathology ; Disease Models, Animal ; Ferroptosis/genetics ; Amyloid beta-Peptides ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Signal Transduction ; },
abstract = {Ferroptosis is an emerging pathological mechanism in Alzheimer's disease (AD). The aim of the present study was to investigate the potential mechanisms by which TARDBP is involved in AD by promoting ferroptosis. An AD rat model was established by injecting homocysteine (Hcy). Memory function was assessed using the Morris water maze test and contextual fear conditioning test. Hippocampal neurons' morphology was observed by HE staining, and intracellular iron deposition in the hippocampus was evaluated by Perls' blue staining. PC12 cells were treated with 20 μM Aβ1-42 to establish an AD cell model in vitro. Cell viability was measured by MTT assay; LDH release, intracellular ROS levels and Fe[2+] concentrations were determined. The mRNA stability of KRAS was assessed by actinomycin D assay. Activation of the MAP3K11/SLC3A2/GPX4 pathway was assessed by Western blot. Treatment with Fer-1 or down-regulation of TARDBP improved memory function and reduced intracellular iron deposition in the hippocampus of AD rats. Furthermore, these interventions inhibited Aβ1-42-induced PC12 cell damage, ROS production and iron accumulation. Mechanistically, down-regulating TARDBP reduced the mRNA stability of KRAS, inhibited MAP3K11 expression and subsequently promoted the expression of SLC3A2 and GPX4. Conversely, up-regulation of KRAS reversed the protective effects induced by TARDBP knockdown in both AD rats and Aβ1-42-induced PC12 cells. TARDBP promotes the development of AD by enhancing the mRNA stability of KRAS, thereby mediating the MAP3K11/SLC3A2/GPX4 axis to induce ferroptosis.},
}

Animals
Rats
*Alzheimer Disease/metabolism/genetics/pathology
PC12 Cells
*RNA Stability/genetics
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics
*Proto-Oncogene Proteins p21(ras)/genetics/metabolism
Male
Hippocampus/metabolism/pathology
Disease Models, Animal
Ferroptosis/genetics
Amyloid beta-Peptides
Reactive Oxygen Species/metabolism
Iron/metabolism
RNA, Messenger/genetics/metabolism
Rats, Sprague-Dawley
Signal Transduction

@article {pmid42145109,
year = {2026},
author = {Saxena, P and Kothiyal, P and Ratan, P},
title = {Evaluation of neuroprotective effects of Pyracantha crenulata (D. Don) M. Roem against aluminium chloride induced memory impairment of rats.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/01616412.2026.2673060},
pmid = {42145109},
issn = {1743-1328},
abstract = {Pyracantha crenulata, traditionally used in Himalayan folk medicine, valued for enhancing vitality, mental clarity, and combating age-related cognitive decline due to its antioxidant constituents.

AIM: This study evaluated the neuroprotective effect of hydroalcoholic extract of P. crenulata against aluminium chloride (AlCl3)-induced Alzheimer's disease in rats.

MATERIALS AND METHODS: Alzheimer's pathology was induced using AlCl3, and rats were treated with P. crenulata extract (250 and 500 mg/kg) for 21 days. Cognitive and behavioural performance were assessed using the Morris Water Maze (MWM) and Elevated Plus Maze (EPM). Biochemical parameters, including oxidative stress markers (SOD), cholinesterase activity (AChE), and myeloperoxidase levels (MPO), were measured. Histopathological examination of the hippocampus and cerebral cortex was conducted.

RESULTS: Aluminium intoxication led to marked deficits in learning and memory, as evidenced by performance in the Morris Water Maze and Elevated Plus Maze tests. Treatment with P. crenulata extract significantly enhanced spatial and long-term memory in a dose-dependent manner, with the higher dose producing the most pronounced improvement.

CONCLUSION: The findings of this study highlight the notable neuroprotective effects of P. crenulata, demonstrated through modulation of biochemical parameters and suppression of amyloid precursor protein and Tau, key pathological hallmarks of Alzheimer's disease, further validated by histopathological evidence.},
}

@article {pmid42145110,
year = {2026},
author = {Wimo, A and Jönsson, L},
title = {[Health economic aspects of dementia].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42145110},
issn = {1652-7518},
mesh = {Humans ; *Dementia/economics/diagnosis/epidemiology ; Sweden/epidemiology ; Cost-Benefit Analysis ; Health Care Costs ; Cost of Illness ; Quality of Life ; Alzheimer Disease/economics ; Life Expectancy ; },
abstract = {The societal costs of dementia in Sweden are very high: about SEK 90-100 billion per year. A purely demographic projection to 2050 gives a cost increase of about 80%. In addition to the costs, dementia also entails a loss of life expectancy for those with dementia and of quality of life for those affected and their relatives. At present, it is not possible to assess whether the antibody treatment against Alzheimer's disease is cost-effective in Sweden because no price is yet available. Blood-based biomarkers for Alzheimer's disease and other diagnostic methods, if included in the pricing basis for new drugs, can be a valuable addition to cost-effectiveness analyses.},
}

Humans
*Dementia/economics/diagnosis/epidemiology
Sweden/epidemiology
Cost-Benefit Analysis
Health Care Costs
Cost of Illness
Quality of Life
Alzheimer Disease/economics
Life Expectancy

@article {pmid42145619,
year = {2026},
author = {Sherva, R and Bayly, H and Zhang, R and Harrington, K and Mez, J and Miller, MW and Tsuang, D and Wolf, E and Zeng, Q and Le Guen, Y and Tejeda, M and , and , and , and Gaziano, JM and Panizzon, MS and Hauger, RL and Merritt, VC and Farrer, LA and Logue, MW},
title = {A Genome-wide Association Study of Alzheimer's Disease and Dementia in a Large Multi-ancestry Military Cohort Identifies Many New Dementia-Associated Loci.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.26352216},
pmid = {42145619},
abstract = {INTRODUCTION: Biobank-scale cohorts of individuals with genetic data and diagnoses of Alzheimer's disease and related dementias (ADRD) have facilitated the discovery of additional risk loci via meta-analysis, with existing cohorts assembled specifically for ADRD genetic discovery. Cross-ancestry meta-analyses have further elucidated the overall genetic architecture of these dementias. Here, we include for the first time the European ancestry (EA) and Hispanic ancestry (HA) subset of the VA Million Veterans Program (MVP) along with the African ancestry (AA) MVP participants in a meta-analysis with a large-scale EA and AA meta-analysis.

METHODS: Independent genome-wide association studies (GWASs) were conducted in MVP participants using four phenotypes derived from electronic medical records and surveys: ADRD, prescriptions for common dementia medications, and self-reported maternal and paternal history of dementia (dementia by proxy). These GWASs were repeated in the EA, AA, and HA cohorts. MVP ancestry-specific and cross-ancestry meta-analyses were conducted. These were then meta-analyzed with existing GWAS results. Functionality of the peak variants was explored using brain-derived gene expression data and co-localization analysis.

RESULTS: Apart from the APOE region, 17, 4, and 3 genome-wide significant (GWS) loci were observed in the MVP EA, AA, and HA meta-analyses, respectively. When we meta-analyzed these with consortium results, we observed 72 loci in the EA GWAS, and 62 lead loci in the cross-ancestry meta-analysis. While most of these loci were known, 27 genes/regions were identified containing variants surpassing genome-wide significance for the first time: 7 EA specific, 12 in the cross-ancestry meta-analysis, and 8 driven by AA and HA cohorts. Several of these are members of pathways containing established ADRD risk genes, and several of the peak SNPs showed evidence for eQTL effects on their respective genes. Several of the novel SNPs showed significant eQTL effects in brain-derived mRNA-seq experiments. Additionally, there was a significant differential expression of the novel gene PAX7 in ADRD cases and controls.

DISCUSSION: MVP represents a large and unique primarily male cohort comprised of US Veterans from a range of backgrounds with a unique set of environmental exposures. The results generated here demonstrate the utility of biobank level cohorts for AD genetic discovery. Furthermore, our discovery of ADRD genes was enhanced by the inclusion of MVP data that provided an increase of underrepresented ancestry groups in contrast to prior cross ancestry GWASs. The new AD risk loci identified present potential new targets for dementia treatment confirmed that future large-scale analyses of AD genetic risk and prediction will be enhanced by the inclusion of MVP data.},
}

@article {pmid42145636,
year = {2026},
author = {Lorenzi, M and Custo, A and Frisoni, GB and Garibotto, V},
title = {A data-driven Alzheimer's disease progression simulator for retrospective validation and prospective Phase III power design.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.26352317},
pmid = {42145636},
abstract = {Anti-amyloid immunotherapies have recently demonstrated the first significant slowing of cognitive decline in Alzheimer's disease (AD), yet clinical benefit varies markedly across drugs and scales with the completeness of amyloid clearance. Pharmacokinetic/pharmacodynamic (PK/PD) models are currently the standard tool for trial simulation, but they typically operate on single biomarkers and rely on drug-concentration assumptions, leaving the multi-scale cascade from amyloid clearance through tau, neurodegeneration, and cognition largely unmodelled. No existing framework has been jointly validated against the quantitative outcomes of multiple real-world phase III trials, spanning clearance kinetics, multi-modal biomarker trajectories, and statistical power. We present a trial simulation platform based on SimulAD, a disease progression model trained exclusively on longitudinal observational data from ADNI, with no access to trial-arm labels or drug-specific outcomes. SimulAD encodes intervention as piecewise amyloid clearance terms within a latent ordinary differential equation system that jointly governs amyloid, tau, structural MRI, and cognitive trajectories under the amyloid cascade hypothesis. We retrospectively simulated six landmark phase III anti-amyloid trials (TRAILBLAZER-ALZ2, CLARITY AD, EMERGE and ENGAGE, GRADUATE I and GRADUATE II) using a single trained model with trial-specific calibration limited to amyloid clearance kinetics. SimulAD reproduced published mean centiloid reductions within 5% error across all six trials and generated CDR-SB distributions broadly consistent with reported placebo and treated-arm outcomes. In a retrospective power analysis, calibrated simulations separated the three positive from the three null trials, with EMERGE near the decision boundary and ENGAGE and both GRADUATE trials below it. Across trials, higher amyloid-clearance rates were associated with larger calibrated clinical effects and lower estimated sample sizes. These results establish SimulAD as a valid disease-progression-centric trial simulator providing quantitative guidance on sample size planning and treatment kinetics optimisation that is grounded in the full multi-modal biomarker cascade of AD.},
}

@article {pmid42146610,
year = {2026},
author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD},
title = {ApoE Lipidation State Directs Immunometabolic Reprogramming of Human Microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722733},
pmid = {42146610},
issn = {2692-8205},
abstract = {INTRODUCTION: ApoE4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free or lipid-bound ApoE3 or ApoE4. Label-free live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged lipid droplets and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to lipid-free ApoE, which was exacerbated by lipid-free ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas lipid-free ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.},
}

@article {pmid42146614,
year = {2026},
author = {Lu, W and Caulfield, TR and Lee, E and Jeevaratnam, S and Wang, N and Bu, G and Kanekiyo, T and Li, Y},
title = {Discovery of a CI-994 derivative as a dual modulator of class I HDACs and Wnt/β-catenin signaling for Alzheimer's disease therapy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.30.721954},
pmid = {42146614},
issn = {2692-8205},
abstract = {Alzheimer's disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC 50 values of 0.51 μM, 0.68 μM, and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC 50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, and suppresses tau phosphorylation in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.},
}

@article {pmid42146852,
year = {2026},
author = {D'Amelio, C and Feroleto, C and Caligiuri, C and Li Puma, DD and De Chiara, G and Paoletti, I and Codazzi, C and D'Alelio, F and Miraglia, F and Pappalettera, C and Nucci, L and Frasca, F and Ventura, L and Manca, A and Morrone, M and Leone, L and Deriu, F and Morotti, M and Grassi, C and Vecchio, F and Podda, MV},
title = {EEG-motor correlation as early Alzheimer's disease index in herpes simplex virus type-1-infected mice.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag128},
pmid = {42146852},
issn = {2632-1297},
abstract = {Alzheimer's disease is a neurodegenerative disorder characterized by cognitive decline and memory impairment. Early treatment requires reliable tests to identify the initial manifestations for developing treatments that modify disease progression. Neuroinflammation has been implicated as a key driver of the onset and progression of Alzheimer's disease. Herpes simplex virus type-1 (HSV-1), a neurotropic virus that establishes latency within the central nervous system, has been associated with increased proinflammatory cytokines, cognitive impairment and Alzheimer's disease-like pathology in human and rodent brains. This study employed a murine model showing an Alzheimer's disease-related phenotype, induced by HSV-1 infection and recurrent reactivation through thermal stress, to investigate previously unexplored motor function impairments and their correlation with EEG changes predictive of Alzheimer's disease-like pathology. Mice were subjected to two (2×TS) or seven thermal stress (7×TS) HSV-1 reactivations to reproduce mild and severe cognitive impairments, respectively, and were tested for recognition memory using the Novel Object Recognition test and for spatial memory using the Y-maze test. Motor performance was assessed using grip strength and grid walking tests. Local field potential recordings, immunohistochemical, morphological and molecular analyses were performed to characterize the effects of HSV-1 on neural circuits. 2×TS HSV-1 mice showed a reduced preference index in Novel Object Recognition compared to mice receiving mock infection (i.e. vehicle inoculum), whereas 7×TS HSV-1 mice displayed severe cognitive decline across the different memory domains. Motor function was preserved after the second thermal stress but was impaired after the seventh thermal stress, with reduced forelimb force and increased foot faults starting from the fourth reactivation. Following the seventh reactivation, HSV-1 mice showed astrogliosis and phosphorylated Tau accumulation. In vivo, electrophysiological recordings revealed increased functional connectivity across frequency bands in 2×TS HSV-1 mice compared to controls, with negative correlations between total coherence and grip strength. Increased spine density in the frontal cortex of 2×TS HSV-1 mice supports early neuronal network alterations. From a translational perspective, we preliminarily evaluated comparable motor indices in healthy human participants, in patients with mild cognitive impairment, and in patients with Alzheimer's disease. As expected, both grip strength and dynamic balance were lower in patients with Alzheimer's disease compared to healthy and mild cognitive impairment subjects. Notably, grip strength was significantly reduced in mild cognitive impairment subjects, who displayed early motor impairment. Our findings highlight the potential of EEG-based biomarkers for early Alzheimer's disease detection and suggest motor indices as novel prognostic markers.},
}

@article {pmid42146883,
year = {2026},
author = {García-Alberca, JM and Mendoza, S and DE LA Guía, P and López DE LA Rica, M},
title = {Effectiveness of Souvenaid® combined with acetylcholinesterase inhibitors on caregiver burden in Alzheimer´s disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70262},
pmid = {42146883},
issn = {2352-8737},
abstract = {INTRODUCTION: The burden experienced by caregivers of Alzheimer´s disease (AD) patients is a complex and stressful situation influenced by distinct variables, such as the patient´s need for monitoring, social isolation, mental or physical health problems, or financial challenges. In additon, behavioral and psychological symptoms of dementia are strongly associated with caregiver experiences of burden.

METHODS: This was a 12-month, retrospective, single-center, real-world study to evaluate the effectiveness of the combined treatment with Souvenaid and acetylcholinesterase inhibitors (AChEI) compared to treatment with either AChEI alone or Souvenaid alone on caregiver burden, anxiety and depression in patients, and AD patients attending a memory clinic. Assessments were conducted using the Zarit Burden Interview (ZBI), the Beck Depression Inventory (BDI), the State Trait Anxiety Inventory-State (STAI-S), and the Neuropsychiatric Inventory-Caregiver distress scale (NPI-D). A mixed model for repeated measures was conducted to evaluate differences from baseline to month 12 between caregivers in the three treatment groups.

RESULTS: At 12 months, caregiver burden, depression, anxiety levels, and the emotional distress in the context of behavioral and psychological symptoms of dementia (BPSD) improved in caregivers in the Souvenaid plus AChEI group (n = 70) compared to those in the AChEI group (n = 84) and those in the Souvenaid group (n = 66).The mean change for the ZBI score was found to be significantly higher in the Souvenaid plus AChEI group than in the AChEI group (p < 0.001) and the Souvenaid group (p < 0.001). In addition, there was a significant difference in the mean change for the BDI, STAI-S, and NPI-D scores between groups, favoring the Souvenaid plus AChEI group over the AChEI and Souvenaid groups.

DISCUSSION: In addition to assessing patients' cognitive, behavioral, and daily functioning, it is recommended regular monitoring of caregiver burden while providing support for patients with dementia. The combined treatment with Souvenaid and AChEI may have a significant impact on caregivers' experience of burden.},
}

@article {pmid42147211,
year = {2024},
author = {Prinz, A and Buerger, D and Krafft, J and Bergmann, M and Woll, A and Barisch-Fritz, B and Witte, K},
title = {Use of Immersive Virtual Reality in Nursing Homes for People With Dementia: Feasibility Study to Assess Cognitive, Motor, and Emotional Responses.},
journal = {JMIR XR and spatial computing},
volume = {1},
number = {},
pages = {e54724},
pmid = {42147211},
issn = {2818-3045},
abstract = {BACKGROUND: Physical activity interventions for people with dementia have shown promising effects in improving cognition and physical function or slowing disease-related decline. Immersive virtual reality (iVR), using head-mounted displays, facilitates realistic experiences by blurring the boundaries between VR and the real world. The use of iVR for people with dementia offers the potential to increase active time and improve dementia therapy and care through exercise interventions. However, the feasibility of using VR use in people with dementia, considering changes in motor, cognitive, psychological, and physiological parameters, remains insufficiently investigated.

OBJECTIVE: This study aims to investigate the feasibility of using iVR in people with dementia or mild cognitive impairment in nursing homes. Specifically, we examined changes in motor performance (balance and mobility), cognitive performance (global cognition and executive functions), emotional responses, and fear of falling using iVR.

METHODS: Utilizing a pre-post design, this study recruited 35 participants with mild-to-moderate dementia, assessed by the Mini-Mental State Examination (MMSE). Participants underwent a single session involving iVR exposure, with pre- and postexposure assessments and a feedback form, to exclude negative effects on cognitive and motor functions, mood, anxiety levels, and balance performance. The use of iVR involved 4 scenes, with a total length of 8 minutes. These scenes depicted a park with short and rather passive impressions presented as a 360° video in a head-mounted display. Before and after using the iVR, cognitive parameters were assessed using the Trail-Making Test A (TMT-A), motor parameters were assessed using the FICSIT-4 (Frailty and Injuries: Cooperative Studies of Intervention Techniques-4) and Timed-Up-and-Go (TUG) tests, and psychological parameters were assessed using the Dementia Mood Picture Test, State-Trait Anxiety Inventory, and Short Falls Efficacy Scale-International (Short FES-I). The Emotion Rating Scale and the duration of use were recorded during use, and a feedback questionnaire was completed afterward in addition to the posttests. Paired t tests and Wilcoxon tests were used to examine pre-post differences.

RESULTS: Of the 35 initial participants, 33 completed the study, which corresponds to a dropout rate of 6%. All 33 participants, who had a mean of 83.71 (SD 5.01) years, had dementia. They showed no statistically significant difference in cognitive and motor performance before and after iVR use. Thus, no negative effects on cognitive and motor functions, mood, anxiety levels, and balance performance were observed. The emotion rating scale also showed that 72% (n=24) felt joy and fun during iVR use, 100% (n=33) showed no emotions such as fear, sadness, or anger, and 93% (n=31) were attentive during iVR use.

CONCLUSIONS: The feasibility of using iVR for people with dementia can be rated positively. There were no changes in motor, cognitive, or emotional parameters that would increase the risk of falls or other negative emotional reactions during or after iVR use. Further studies are needed to investigate prolonged use in a more stimulating computer-generated environment and possible physical and cognitive tasks for people with dementia in nursing homes.

TRIAL REGISTRATION: German Clinical Trials Register DRKS00030616; https://drks.de/search/de/trial/DRKS00030616.},
}

@article {pmid42147344,
year = {2026},
author = {Geerts, H and Short, SM and Grant, A and van der Graaf, PH},
title = {Understanding quantitative effects of anti-amyloid therapies on tau biomarkers and functional outcome. Insights from a comprehensive mechanistic quantitative systems pharmacology study.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1813290},
pmid = {42147344},
issn = {1663-9812},
abstract = {INTRODUCTION: Anti-amyloid antibodies have the potential to become the standard of care in Alzheimer's Disease (AD) and large datasets from clinical trials allow the testing of predictive models on fluid biomarkers and functional outcomes. However, identifying an easily accessible biomarker to determine the time to switch to maintenance therapy, and identifying patient profiles with optimal cognitive benefit, are still unresolved issues in clinical practice.

METHODS: Predicted changes in monomers, oligomers, protofibrils and plaques were simulated using a well-validated Quantitative Systems Pharmacology model based on biophysical and biological assumptions of amyloid synthesis, aggregation and clearance. This model was combined with a previously calibrated computational neuronal network model of cognitive outcome in AD patients by introducing the effect of amyloid and tau oligomers on specific voltage- and ligand-gated ion channels, informed by preclinical studies.

RESULTS: The model accounted for 70% and 50% of the variance of clinically observed changes in plasma p-tau181 and Clinical Dementia Rating-Sum Of Boxes (CDR-SOB) respectively, in clinical trials of seven amyloid antibodies. We derived an antibody specific normalized decrease of plasma p-tau181 (-15% for donanemab, -45% for aducanumab and -75% for lecanemab) to determine trial duration for achieving central amyloid negativity. Using the concept of information processing bandwidth, the model suggests that anti-amyloid antibodies slow the cognitive worsening compared to placebo while at the same time lowering plasma p-tau181 levels by reducing neuronal firing. Finally, the model suggests that independently from the degree of amyloid reduction, the beneficial cognitive effect of treatment decreases with more advanced neuronal pathology and higher baseline tau-load. This provides a hypothesis for the impact of disease pathology and gender effect on functional outcomes with lecanemab and gantenerumab.

DISCUSSION: With further validation, this model has the capability to support optimization of clinical trial design for amyloid-tau combination therapy.},
}

@article {pmid42147618,
year = {2026},
author = {Sewell, DD and Kallenberg, G and Mandel, B and Mandvi, A and Asmus, L and Neel, IC and Heimler, G and Andrew, W and Lobatz, M},
title = {Enhancing Dementia Care in Primary Care: Impact of Targeted Training and Electronic Medical Record (EMR)-Integrated Algorithms.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e107031},
pmid = {42147618},
issn = {2168-8184},
abstract = {INTRODUCTION: The number of medical specialists whose training programs provide robust education in dementia diagnosis and treatment pales in comparison to the increasing number of individuals living with dementia. Primary care providers (PCPs) care for most older adults with cognitive concerns and dementia. Summarized here are the results of an effort to help PCPs care for these patients using targeted training and electronic medical record (EMR)-integrated clinical algorithms.

METHODS: Clinicians from two University of California San Diego Family Medicine Clinics completed assessments of dementia knowledge and comfort in caring for patients and family members impacted by dementia four times: enrollment, and approximately two, nine and 15 months after a three-component intervention: 1) training via four online educational modules (six hours total) on screening, evaluation, and care of patients with dementia; 2) integration of clinical algorithms into the EMR system and 3) access to mentoring from a more experienced peer.

RESULTS: Subjective assessment of comfort and competence of intervention group clinicians in working with patients with cognitive complaints significantly increased and was higher for intervention group PCPs than the comparison group PCPs. Evidence of completed AD8s (Eight-Item Informant Interview to Differentiate Aging and Dementia) at both clinics increased from baseline to post-intervention: 52.85% to 82.6% and 66.1% to 86.9%.

DISCUSSION: Training PCPs on dementia screening and diagnosis, and integration of algorithms into the EMR, improved clinician subjective competence and comfort in caring for patients with cognitive complaints and increased the AD8 completion rate. The small number of study participants mandates caution when interpreting these findings.},
}

@article {pmid42148080,
year = {2026},
author = {You, J and Liu, Q and Li, X},
title = {Anti-Aβ3-10 monoclonal antibody 7B8 improves cognitive function and protects the blood-brain barrier in APP/PS1 mice by regulating the HMGB-1/RAGE/NF-κB pathway.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1781351},
pmid = {42148080},
issn = {1664-3224},
mesh = {Animals ; *Blood-Brain Barrier/drug effects/metabolism/immunology ; Mice ; Mice, Transgenic ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy/immunology ; *Cognition/drug effects ; Amyloid beta-Protein Precursor/genetics ; NF-kappa B/metabolism ; Signal Transduction/drug effects ; HMGB1 Protein/metabolism ; Disease Models, Animal ; *Antibodies, Monoclonal/pharmacology ; Presenilin-1/genetics ; Receptor for Advanced Glycation End Products/metabolism ; Male ; Mice, Inbred C57BL ; Humans ; *Peptide Fragments/immunology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent dementia, is primarily underpinned by the amyloid cascade hypothesis. Passive Aβ immunotherapy effectively reduces cerebral Aβ deposition but is limited by severe side effects, including cerebral amyloid angiopathy (CAA), microhemorrhage, and amyloid-related imaging abnormalities (ARIA). Here, we investigated the efficacy and safety of a novel anti-A3-10 monoclonal antibody (7B8) in APP/PS1 double-transgenic mice, with a focus on its impacts on amyloid clearance, neuroinflammation, and blood-brain barrier (BBB) integrity.

METHODS: 7B8 was generated by immunizing mice with A3-10-KLH. Six-month-old APP/PS1 mice were intraperitoneally injected with 7B8 (10 mg/kg) weekly for 8 doses (7B8 group). Age-matched APP/PS1 mice treated with IgG and C57BL/6J mice served as negative and wild-type (WT) controls, respectively. One week after the final injection, behavioral tests were performed, followed by euthanasia for histological (left brain hemisphere) and biochemical (right brain hemisphere) analyses.

RESULTS: Compared with the IgG group, the 7B8 group exhibited significantly reduced cerebral Aβ deposition and improved cognitive function (both P < 0.05), comparable to the WT group. Notably, in these young 6-month-old APP/PS1 mice with early-stage amyloid deposition and minimal CAA pathology, 7B8 treatment did not increase microhemorrhage risk relative to the IgG control group (P > 0.05). Furthermore, 7B8 preserved vascular integrity by reducing perivascular Aβ40 deposition and smooth muscle actin damage, while enhancing endothelial cell fluorescence intensity (P < 0.05). At the molecular level, 7B8 upregulated vascular LRP-1 and BBB tight junction proteins (ZO-1, CLDN-5, Occludin), and downregulated RAGE expression (P < 0.05). It also suppressed microglial and astrocytic activation, reduced levels of IL-6 and cortical TNF-α, and inhibited the HMGB-1/RAGE/NF-κB signaling pathway (P < 0.05), without affecting global TNF-α or IL-1β levels.

CONCLUSION: 7B8 effectively alleviates cognitive impairment and clears cerebral and perivascular amyloid deposits in young APP/PS1 mice with early-stage AD pathology and minimal CAA, with no increased risk of microhemorrhage in this experimental setting. It also protects vascular structure and BBB integrity by inhibiting the HMGB-1/RAGE/NF-κB-mediated neuroinflammatory response. Given the limitations of evaluating CAA-related safety in young mice, future studies using mid-aged (12-15-month-old) APP/PS1 mice with prominent CAA will be conducted to fully characterize 7B8's safety profile. These findings highlight 7B8 as a promising candidate for safe and effective AD immunotherapy, providing new insights into the development of ARIA-minimizing strategies.},
}

Animals
*Blood-Brain Barrier/drug effects/metabolism/immunology
Mice
Mice, Transgenic
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
*Alzheimer Disease/metabolism/drug therapy/immunology
*Cognition/drug effects
Amyloid beta-Protein Precursor/genetics
NF-kappa B/metabolism
Signal Transduction/drug effects
HMGB1 Protein/metabolism
Disease Models, Animal
*Antibodies, Monoclonal/pharmacology
Presenilin-1/genetics
Receptor for Advanced Glycation End Products/metabolism
Male
Mice, Inbred C57BL
Humans
*Peptide Fragments/immunology

@article {pmid42148242,
year = {2025},
author = {Khazaneha, M and Khadir, E and Motaghi, N and Arvan, H and Ebrahimi-Meimand, HA},
title = {Scientometric insights into neurology publications in Iran.},
journal = {Current journal of neurology},
volume = {24},
number = {1},
pages = {87-96},
pmid = {42148242},
issn = {2717-011X},
abstract = {Background: Undoubtedly, medical science has been born since the beginning of human creation. One of its important branches is neurology. Neurosciences in Iran, with a little delay from the first world, with the efforts of researchers, opened the way for the diagnosis and treatment of neurological diseases, and we reached the place where we are. Methods: In this bibliometric and scientometric study, we have evaluated the process of neurological science in Iran. By referring to the reliable indexes, we checked Web of Science (WoS), PubMed, and Scopus from 1963 onwards. We showed the published activities of Iranians in the form of charts and tables. Results: This study indicates the increasing growth of scientific studies in the field of neurology. In the field of neuroscience, the researchers are mostly aimed at the education and training of specialists and PhD students, and depending on the research facilities, as well as acquaintances and connections for the publication of articles. Diseases that have afflicted a large number of people causing them to suffer and limiting their activities, such as multiple sclerosis (MS), Alzheimer's, epilepsy, Parkinson's, and brain strokes have been the focus of researchers. Conclusion: Neurological studies have an increasing trend and can be divided into two basic sections, which are mainly done by neuroscientists and are based on the educational needs and training of specialists, but neurology studies and scientific publications are mainly done by neurologists and based on feeling the need and diseases in this field have been done.},
}

@article {pmid42148368,
year = {2026},
author = {Bailey-Taylor, MJ and Morrow, P and Hendrix, J and Galluzzi, KE and Sharafsaleh, G},
title = {Therapeutic Landscape of Early Symptomatic Alzheimer's Disease Translated into Everyday Practice for Geriatric Providers.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {585263},
pmid = {42148368},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; Aged ; Cognitive Dysfunction/drug therapy ; Disease Progression ; Biomarkers ; },
abstract = {Alzheimer's disease (AD) accounts for 60-80% of all dementia cases. Recent advances in diagnostic biomarkers of early symptomatic AD (ie, mild cognitive impairment and mild dementia due to AD) and amyloid-targeting therapies (ATTs) have the potential to improve outcomes for patients with AD. Two ATTs (donanemab and lecanemab) are currently approved and available for use in the US. Both ATTs can slow disease progression as well as cognitive and functional decline in patients with early symptomatic AD. Treatment with ATTs is associated with specific safety concerns such as amyloid-related imaging abnormalities. Therefore, the benefit versus risk profile needs to be carefully considered when deciding whether to treat a patient with ATTs. This review aims to educate geriatric-trained health professionals regarding advances in the diagnosis and treatment of early symptomatic AD, including the optimal duration of treatment, management of adverse reactions, and patient counseling. It also discusses key considerations in care transitions and patient management in multidisciplinary settings to ensure continuous patient-centered care.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis
Aged
Cognitive Dysfunction/drug therapy
Disease Progression
Biomarkers

@article {pmid42148603,
year = {2026},
author = {Xu, Q and Lu, J and Zhang, Z and Xu, D and Guo, C},
title = {Deep learning-based cognitive impairment brain imaging analysis: New methods, new technologies, and new paradigms.},
journal = {Neural regeneration research},
volume = {21},
number = {9},
pages = {4135-4147},
doi = {10.4103/NRR.NRR-D-25-00332},
pmid = {42148603},
issn = {1673-5374},
abstract = {Cognitive impairment arising from ischemic stroke, Alzheimer's disease, and Parkinson's disease presents distinct structural and network-level alterations. Brain magnetic resonance imaging offers a non-invasive and high-resolution approach to assess these changes, while deep learning provides powerful tools for automated analysis. Given that accurate lesion delineation, precise localization of abnormal regions, and reliable disease classification are fundamental to clinical decision-making. This review aims to explore the application of deep learning techniques to brain magnetic resonance imaging analysis of cognitive impairments caused by these disorders, with a focus on three core tasks: lesion segmentation, object detection, and image classification. Recent widely accepted findings indicate that ischemic stroke studies have achieved state-of-the-art lesion segmentation performance, with optimized U-shaped convolutional network (U-Net) and hybrid convolutional neural network-transformer models reaching Dice scores up to 0.911 in delineating focal damage. Alzheimer's disease research has advanced classification and staging accuracy by more than 10% compared with unimodal baselines through three-dimensional convolutional neural network, Transformers, and multimodal fusion, enabling more precise detection of diffuse cortical atrophy. Parkinson's disease imaging, despite lacking overt structural lesions, has leveraged ResNet and Vision Transformer backbones to identify subtle and spatially distributed abnormalities, improving early-stage differentiation. Persistent challenges include the scarcity of large, high-quality annotated datasets, substantial inter-site variability, high annotation costs, and limited interpretability, hindering clinical integration. Addressing these barriers will require advances in federated learning to mitigate data scarcity while preserving privacy, domain adaptation techniques to reduce inter-site variability, automated annotation, and low-resource training strategies to lower labeling costs, and explainable artificial intelligence to improve interpretability, thereby ensuring model robustness, privacy, and transparency. This review highlights emerging methods, innovative technologies, and novel paradigms that are redefining brain imaging analysis in cognitive impairment. Mechanistically, deep learning improves cognitive impairment analysis by integrating hierarchical and multiscale spatial features, modeling long-range functional connectivity disruptions, and fusing structural with functional imaging to better represent network-level pathology. In conclusion, aligning network architectures with disease-specific imaging characteristics and task requirements can greatly enhance the accuracy, robustness, and generalizability of magnetic resonance imaging analyses for cognitive impairment. Future work should focus on multimodal fusion, structure-function coupling, cross-disease evaluations, and embedding artificial intelligence tools into clinical workflows to support early detection, individualized treatment planning, and large-scale clinical adoption.},
}

@article {pmid42138018,
year = {2026},
author = {Chen, CP and Zhang, T and E, ED and Xu, TY and Han, Q and Gao, X and Sun, J and Huang, Y and Yang, JH and Zhang, XQ},
title = {Targeting mGluR2/3 Signaling With LY341495 Restores Dentate Gyrus Function and Cognitive Performance in a Male Mouse Model of Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {5},
pages = {e70916},
pmid = {42138018},
issn = {1755-5949},
support = {82201322//National Natural Science Foundation of China/ ; LY24H090001//the Natural Science Foundation of Zhejiang Province/ ; 2024010317//Ningbo Top Medical and Health Research Program/ ; 2022020304//Ningbo Top Medical and Health Research Program/ ; 2023H017//Ningbo Science and Technology Project/ ; 2024L003//Ningbo Clinical Research Center for Emergency and Critical Diseases/ ; },
mesh = {Animals ; Male ; *Alzheimer Disease/drug therapy/pathology/genetics/metabolism/psychology ; *Receptors, Metabotropic Glutamate/antagonists & inhibitors/metabolism ; *Dentate Gyrus/drug effects/metabolism ; Mice, Transgenic ; Mice ; Disease Models, Animal ; *Xanthenes/pharmacology/therapeutic use ; *Amino Acids/pharmacology/therapeutic use ; *Cognition/drug effects ; Signal Transduction/drug effects ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Aberrant metabotropic glutamate receptor 2/3 (mGluR2/3) signaling has been implicated in the synaptic and cognitive deficits observed in Alzheimer's disease (AD), yet the underlying regulatory mechanisms remain unclear. This study investigated the therapeutic potential of LY341495, a selective mGluR2/3 antagonist, in APP/PS1 transgenic mice, a widely used AD model.

METHODS: Male APP/PS1 mice were treated with the selective mGluR2/3 antagonist LY341495. Cognitive performance was evaluated using behavioral tests. Hippocampal dentate gyrus (DG) alterations were examined by immunohistochemistry and electrophysiology, including analyses of mGluR2/3 expression, excitatory synaptic activity, adult neurogenesis, calbindin expression, and amyloid-β plaque burden.

RESULTS: APP/PS1 mice exhibited pathological upregulation of mGluR2/3 in the DG, accompanied by altered presynaptic glutamatergic transmission, reduced neurogenesis, decreased calbindin expression, and deficits in recognition and spatial memory. LY341495 treatment attenuated the aberrant mGluR2/3 upregulation, enhanced excitatory synaptic activity, and improved calbindin levels and neurogenesis in the DG. Importantly, these changes were associated with significant reductions in DG amyloid-β plaque burden and marked improvements in cognitive performance.

CONCLUSIONS: This study highlights the novelty of linking mGluR2/3 inhibition to the restoration of calcium-buffering capacity, as reflected by calbindin expression and neurogenesis, processes critical for DG plasticity and resilience. These findings underscore the therapeutic potential of LY341495 as a novel intervention targeting mGluR2/3 signaling in AD.},
}

Animals
Male
*Alzheimer Disease/drug therapy/pathology/genetics/metabolism/psychology
*Receptors, Metabotropic Glutamate/antagonists & inhibitors/metabolism
*Dentate Gyrus/drug effects/metabolism
Mice, Transgenic
Mice
Disease Models, Animal
*Xanthenes/pharmacology/therapeutic use
*Amino Acids/pharmacology/therapeutic use
*Cognition/drug effects
Signal Transduction/drug effects
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Mice, Inbred C57BL

@article {pmid42139159,
year = {2026},
author = {Carvalho, MS and Barssotti, L and Santos, LMBD and Rosa, LRO and Gomes-Marcondes, MCC and Carneiro, EM and Barbosa, HCL and Zangerolamo, L},
title = {Tauroursodeoxycholic acid (TUDCA) ameliorates age-related skeletal muscle loss.},
journal = {The Journal of physiology},
volume = {},
number = {},
pages = {},
doi = {10.1113/JP290683},
pmid = {42139159},
issn = {1469-7793},
support = {2021/13917-6//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
abstract = {Ageing leads to changes in body composition, including increased adiposity and reduced skeletal muscle mass and force. The alterations in ageing skeletal muscle result from impaired proteostasis driven by factors such as chronic inflammation, hormonal changes and reduced nutrient absorption. Those age-related changes in body composition and skeletal muscle compromise mobility and increase the risk of falls, fractures and metabolic disorders. Tauroursodeoxycholic acid (TUDCA), a bile acid with known benefits in chronic diseases, has been shown by our group to improve cognition and metabolic homeostasis in ageing and Alzheimer's disease mouse models. Interestingly, in previous studies, TUDCA treatment was also associated with increased skeletal muscle mass in ageing mice, leading us to hypothesize that TUDCA could target skeletal muscle to reduce age-related muscle loss. To explore this, we treated 18-month-old C57BL/6 mice with TUDCA or vehicle for 20 days, using 3-month-old mice as a young control group. We demonstrate that TUDCA treatment decreases body weight while increasing skeletal muscle mass, restores muscle fibre size and preserves functional integrity. Additionally, TUDCA enhances skeletal muscle insulin sensitivity through increased AKT activation and reduces tissue inflammation. Such improvements collectively support the restoration of skeletal muscle proteostasis, as indicated by increased protein synthesis and phosphorylation of key anabolic signalling pathways, including ribosomal protein S6 kinase beta-1 (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These findings contribute to a better understanding of TUDCA's actions on skeletal muscles of ageing mice and highlight its role as a promising strategy against age-related muscle loss. KEY POINTS: Tauroursodeoxycholic acid (TUDCA) treatment attenuates skeletal muscle loss in ageing mice. TUDCA improves skeletal muscle insulin sensitivity and restores AKT signalling. TUDCA exerts an anti-inflammatory effect in skeletal muscle of ageing mice. TUDCA emerges as a potential therapy for age-related skeletal muscle loss.},
}

@article {pmid42139977,
year = {2026},
author = {Soni, U and Pujari, R},
title = {Gentisic acid confers multimodal neuroprotection in experimental Alzheimer's disease by targeting oxidative stress, neuroinflammation, and protein aggregation.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {156},
number = {},
pages = {158276},
doi = {10.1016/j.phymed.2026.158276},
pmid = {42139977},
issn = {1618-095X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with oxidative stress, neuroinflammation, cholinergic dysfunction, and accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (p-tau). Given the multifactorial nature of AD, phytochemicals with multi-target pharmacological properties are of growing therapeutic interest. Gentisic acid (GA; 2,5-dihydroxybenzoic acid) possesses established antioxidant and anti-inflammatory activities; however, its potential relevance in AD has not been comprehensively evaluated.

PURPOSE: This study investigated the neuroprotective potential of gentisic acid against Alzheimer-like pathology using integrated in vitro and in vivo experimental models.

STUDY DESIGN: A preclinical experimental study combining cell-based assays and an aluminium chloride (AlCl3) and D-galactose (D-Gal)-induced rat model of AD-like neurodegeneration was conducted.

METHODS: Blood-brain barrier (BBB) permeability of GA was assessed using a PAMPA-BBB assay. Neuroprotective effects were examined in AlCl₃-exposed SH-SY5Y cells. In vivo, Wistar rats received AlCl₃ and D-Gal to induce cognitive and biochemical alterations, followed by oral GA treatment. Behavioral paradigms such as open field, Morris water maze, novel object recognition, elevated plus maze and Y-maze tests were employed to assess spatial learning, recognition memory, and anxiety-like behavior. Oxidative stress markers, antioxidant enzymes, acetylcholinesterase activity, monoaminergic neurotransmitters, brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines, amyloid beta, and hyperphosphorylated tau protein levels were quantified. Histopathological evaluation of hippocampal and cortical regions was performed.

RESULTS: GA demonstrated adequate BBB permeability and concentration-dependent protection against AlCl₃-induced cytotoxicity in SH-SY5Y cells. In the rat model, GA (10, 30, and 100 mg/kg, per oral (p.o.) improved cognitive performance and attenuated anxiety-like behavior. Treatment with GA reduced lipid peroxidation (malondialdehyde), restored antioxidant defenses (superoxide dismutase, catalase and reduced glutathione), inhibited acetylcholinesterase activity, and normalized monoaminergic neurotransmitters (serotonin and dopamine). GA further elevated BDNF levels and suppressed pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta). Notably, GA decreased cerebral Aβ and p-tau accumulation and preserved hippocampal and cortical architecture.

CONCLUSION: Gentisic acid exerts multi-modal neuroprotective effects, including antioxidant, anti-inflammatory, anti-cholinesterase, and anti-amyloidogenic actions, in experimental models of AD. These findings support its potential as a phytochemical candidate for further development in the prevention or adjunctive management of AD.},
}

@article {pmid42141012,
year = {2026},
author = {Gorin, BI and Pozdnyakov, SO and Potapova, KA and Tukhovskaya, EA and Gorchakov, DS},
title = {Efficacy and safety of DMB-I (latrepirdine) therapy in mild to moderate dementia in Alzheimer's disease: results of a multicenter, double-blind, randomized, placebo-controlled, clinical trial in three parallel groups.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42141012},
issn = {2045-2322},
abstract = {Alzheimer’s disease (AD) is one of leading dementia causes, affecting over 50 million people worldwide. A multicenter, double-blind, randomized, placebo-controlled clinical trial in three parallel groups was conducted to evaluate efficacy and safety of Latrepirdine polymorph DMB-I in 26-week treatment of dementia in patients with AD. 135 patients of both sexes aged 60 to 90 years were randomized into three groups: DMB-I + placebo, 30 mg/day; DMB-I, 60 mg/day and Placebo. Treatment efficacy was assessed using Alzheimer’s disease Assessment Scale cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE-2), quality of life questionnaire (QOL-AD), Clinical Global Impression scale (CGI) and Instrumental Activities of Daily Living score (IADL). Clinical parameters and adverse events (AEs) also assessed. The efficacy of DMB-I at a dose of 60 mg/day was demonstrated by assessing the primary efficacy criterion, namely, a significant change in the ADAS-cog score after 26 weeks of treatment compared with baseline. Severity of cognitive impairment dynamics on ADAS-cog, CGI and LADL scales was significantly improved in groups receiving DMB-I at both doses, compared with placebo. AEs overall incidence was similar between DMB-I and Placebo groups. 26-week therapy with DMB-I at both doses demonstrated efficacy and favorable safety profile. 60 mg/day dose was selected as optimal dose for further studies. Study retrospectively registered on Clinicaltrials.gov on February 27, 2024, NCT06292351.},
}

@article {pmid42141074,
year = {2026},
author = {Cai, C and Chong, YS and Liang, H and Hu, Y and Hu, Q and Chen, J and Sajikumar, S and Liu, F},
title = {Simvastatin rescues cognitive impairment in an Aβ1-42-induced model of Alzheimer's disease through the HDAC2-BDNF signaling pathway.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42141074},
issn = {1740-634X},
support = {2021J011433//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; 82201668//National Natural Science Foundation of China (National Science Foundation of China)/ ; MOH-000641-00//MOH | National Medical Research Council (NMRC)/ ; MOH-001883-00//MOH | National Medical Research Council (NMRC)/ ; },
abstract = {Statins, renowned for their efficacy in treating cardiovascular diseases, have emerged as potential therapeutic agents for the prevention of Alzheimer's disease (AD). Among them, simvastatin (SV) has attracted considerable attention for its reported cognitive benefits in AD. However, the precise mechanisms by which SV modulates spatial cognitive function in AD remain unclear. In the present study, we used an AD model induced through intracerebroventricular administration of Aβ1-42 in male C57BL/6 mice. The cognitive performance were assessed using the Morris Water Maze (MWM) test, the Y-maze and the Novel Object Recognition (NOR) test. HDAC2 and BDNF expression levels were analyzed by Western blotting. Chromatin immunoprecipitation (ChIP) assays were performed to examine histone H4 acetylation (Ac-H4K5) at Bdnf promoters. Our results showed that SV treatment reversed cognitive impairments induced by Aβ1-42. Aβ1-42 administration increased HDAC2 expression, reduced histone H4 acetylation, and decreased BDNF levels in the dorsal hippocampus (dHPC), all of which were restored by SV treatment. Notably, viral overexpression of HDAC2 abolished the beneficial effects of SV, underscoring the critical role of HDAC2 in mediating its actions. Furthermore, blockade of BDNF signaling using TrkB-Fc attenuated the behavioral improvements induced by SV. In addition, SV treatment ameliorated Aβ1-42-induced deficits in neurogenesis and long-term potentiation (LTP). Together, these findings highlight the therapeutic role of SV in AD through epigenetic and synaptic mechanisms, and support further investigation into its clinical applicability.},
}

@article {pmid42141084,
year = {2026},
author = {Shahat, EA and Ayoub, IM and Bakr, RO and Gad, HA and Eldahshan, OA and Singab, ANB},
title = {Comparative analysis of volatile composition and anticholinesterase activity of Egyptian Hedychium coronarium and Alpinia zerumbet using chemometric assessment of extraction techniques.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42141084},
issn = {2045-2322},
mesh = {*Zingiberaceae/chemistry ; *Alpinia/chemistry ; *Oils, Volatile/chemistry/pharmacology/analysis/isolation & purification ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; Plant Leaves/chemistry ; Gas Chromatography-Mass Spectrometry ; Rhizome/chemistry ; *Plant Extracts/chemistry/pharmacology ; Antioxidants/pharmacology/chemistry ; Chemometrics ; Egypt ; },
abstract = {Hedychium coronarium and Alpinia zerumbet are rhizomatous plants belonging to the family Zingiberaceae. They are rich in essential oils. Hydrodistillation and headspace (HS) were employed for the extraction of the essential oils from the leaves and rhizomes of both plants. Essential oils were then analysed by GC/MS and the obtained results were subjected to chemometric analysis. The oil samples obtained by hydrodistillation were tested for their antioxidant and anti-cholinesterase activities using oxygen radical antioxidant capacity assay and colorimetric inhibition kit, respectively. Hydro-distilled oil from H. coronarium leaves showed the presence of forty-seven compounds (97.73%) compared to sixteen compounds (99.17%) in the HS volatiles. Meanwhile, hydro-distilled oil from H. coronarium rhizomes showed the presence of thirty-nine components (95.84%) compared to fifteen compounds (98.68%) in the HS volatiles with 1,8-cineole (41.69% and 58.41%) as the major component in both samples. A. zerumbet leaves oil showed the presence of nineteen compounds (94.54%) in the hydrodistilled oil and twenty-one compounds (99.53%) in the HS volatiles. Besides, the rhizomes hydrodistilled essential oil showed twenty-three compounds (91.85%) and sixteen compounds (100%) in the HS with 1,8-cineole (20.78% and 23.63%) representing the major component in both samples. Chemometric analysis of the results provided a clear and statistically robust discrimination between the hydrodistilled and headspace-isolated oil samples demonstrating that extraction method is a primary determinant of volatile profile. Principal component analysis score plot explained 75% of total variance and distinctly separated samples into four main clusters with key discriminating components β-pinene, and caryophyllene were the major responsible for the segregation of H. coronarium leaves by headspace and hydrodistillation extraction methods, respectively, besides, 1,8-cineole accounted for the discrimination of H. coronarium rhizomes extracted by hydrodistillation. Hierarchial cluster analysis (HCA) fully supported this classification, confirming consistent grouping patterns across both analyses. Importantly, A. zerumbet oils from both extraction methods clustered closely, indicating compositional stability, whereas H. coronarium samples showed strong method-dependent divergence. A. zerumbet rhizomes oil showed the strongest activity as anticholinesterase with IC50 of 0.54 ± 0.02 µg/mL while H. coronarium rhizomes showed the strongest antioxidant activity (10.06 ± 0.16 TE µM/L). H. coronarium leaves and A. zerumbet rhizomes showed anticholinesterase and antioxidant activities to such an extent that may make them a useful adjuvant in the treatment of cognitive diseases such as Alzheimer's.},
}

*Zingiberaceae/chemistry
*Alpinia/chemistry
*Oils, Volatile/chemistry/pharmacology/analysis/isolation & purification
*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification
Plant Leaves/chemistry
Gas Chromatography-Mass Spectrometry
Rhizome/chemistry
*Plant Extracts/chemistry/pharmacology
Antioxidants/pharmacology/chemistry
Chemometrics
Egypt

@article {pmid42142416,
year = {2026},
author = {Chiba, Y and Ide, K and Suzuki, S and Taguri, M and Suzuki, H and Abe, K and Yoshimi, A and Okuda, T and Saito, K and Mizushima, S and Yamanaka, T and Hishimoto, A and Sakurai, T and Arai, H and Asami, T and Odawara, T},
title = {Multimodal intervention benefits: Responder analysis of J-MINT PRIME Kanagawa trial.},
journal = {Archives of gerontology and geriatrics},
volume = {149},
number = {},
pages = {106289},
doi = {10.1016/j.archger.2026.106289},
pmid = {42142416},
issn = {1872-6976},
abstract = {INTRODUCTION: The J-MINT PRIME Kanagawa trial was an 18-month multimodal intervention (incorporating exercise, nutrition, and metabolic management) for dementia prevention. Because the primary analysis showed no significant benefits, we performed an exploratory responder analysis to identify responsive subpopulations.

METHODS: We analyzed the Full Analysis Set comprising 188 participants. Classification and regression tree (CART) analysis, applied to the intervention arm, identified baseline predictors of cognitive improvement. These rules were then applied to the entire cohort to evaluate treatment effects on the Mini-Mental State Examination (MMSE) using fully adjusted mixed-effects models for repeated measures (MMRM).

RESULTS: CART identified a "Target Group" (N = 108) characterized by baseline profiles such as an MMSE score < 28 or specific metabolic ranges (e.g., LDL-C < 135 mg/dL). Within this target group, the intervention significantly preserved MMSE trajectories compared with the control group (group × time interaction, P = 0.022). In contrast, the Non-Target Group (N = 80), consisting of high-functioning individuals (MMSE ≥ 28), exhibited no significant group × time interaction.

DISCUSSION: Multimodal interventions may effectively preserve global cognition in older adults with sub-threshold cognitive decline. Careful targeting of appropriate populations, while considering potential longitudinal measurement artifacts (e.g., practice effects), is essential. These findings provide a hypothesis-generating framework that warrants external validation in future prevention trials.},
}

@article {pmid42134046,
year = {2026},
author = {Chu, TDX and Hui, LM and Khatri, N and Jean Chen, J},
title = {Resilience to mid-to-late-life depression as a risk factor for Alzheimer's disease: Physiological factors and the role of neuroimaging.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {1-13},
doi = {10.1016/j.neurobiolaging.2026.05.004},
pmid = {42134046},
issn = {1558-1497},
abstract = {Depression and Alzheimer's Disease (AD) are both diagnosed in women twice as often as in men. Moreover, a history of untreated depression confers a 2-to-5-fold increase in the risk of developing dementia. Finally, biological factors such as sex differences in immune response increase rates of depressive pathology among women. Importantly, the prevalence of mid-to-late-life depression (MLD) worldwide and its misdiagnosis due to clinical overlap with AD hinder accurate assessment and timely treatment of depression among older adults. Correct diagnosis of depression and AD using neuroimaging will enable early adoption of appropriate management, which will improve cognitive resilience. In the context of neural resilience in late-life depression, this review discusses the involvement of sex-related risk factors such as differences in immune response, and the importance of understanding the mid-life neurological signature of depression. We focus on the role of diffusion-weighted magnetic resonance imaging (MRI), which is also specifically linked to the presence of neuroinflammation in depression and the ability to distinguish it from AD despite cognitive overlaps in clinical manifestation. This review highlights the importance of sex differences in promoting resilience against MLD and AD-related declines, and supports neuroimaging as a feasible approach to advance our understanding of the role of neuroinflammation in both depression and Alzheimer's disease as a sex-dependent phenomenon.},
}

@article {pmid42134309,
year = {2026},
author = {Lee, J and Zhu, Y and Tseng, HR},
title = {Bioorthogonal Click Chemistry-Enabled Enrichment of Extracellular Vesicles for Integrated Molecular and Functional Liquid Biopsy§.},
journal = {Accounts of chemical research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.accounts.6c00091},
pmid = {42134309},
issn = {1520-4898},
abstract = {ConspectusExtracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released by virtually all cells, carrying protected lipids, nucleic acids, proteins, and active enzymes that faithfully reflect the physiological and pathological states of their cellular origins. Tumor- and neuron-derived EVs are abundantly present in peripheral blood, even at early disease stages, and thus represent highly attractive substrates for liquid biopsy. However, the clinical translation of EV-based diagnostics has been constrained by a central challenge: the inability to selectively enrich disease-relevant EVs from a vast background of normal EVs with sufficient specificity, efficiency, and compatibility for seamless integration with downstream molecular and functional analyses. Conventional physical isolation approaches generate heterogeneous EV mixtures that dilute disease-specific signals, whereas traditional immunoaffinity capture often suffers from nonspecific interactions and low recovery due to sparse and heterogeneous antigen density on EV membranes.To overcome these limitations, our laboratory has developed a chemical biology solution utilizing the bioorthogonal inverse-electron-demand Diels-Alder reaction between trans-cyclooctene (TCO) and tetrazine (Tz). By labeling tumor or neuronal EVs in plasma with TCO-grafted antibodies and covalently immobilizing them onto Tz-functionalized substrates, our three EV enrichment platforms, namely, EV Click Chips, EV Click Beads, and EV Click MagBeads, enable rapid, irreversible, and highly specific capture of defined EV subpopulations. These click chemistry-mediated enrichment strategies reduce nonspecific binding, markedly improve capture efficiency, and preserve EV integrity, providing a robust foundation for downstream genetic, proteomic, and functional analyses. Building on this chemical biology solution, we established three complementary EV assay modalities. Platform #1, the EV Digital Scoring Assay, couples click chemistry-mediated EV enrichment with RT-digital PCR to quantify tumor-specific mRNAs or oncogenic mutations. This "enrich-then-count" strategy has demonstrated strong clinical utility in early detection of hepatocellular carcinoma (HCC), molecular staging of prostate cancer, and detection of actionable gene alterations in pancreatic cancer and Ewing sarcoma. A refined version enables real-time HCC treatment-response monitoring, outperforming serum AFP and radiographic criteria in monitoring treatment responses. Platform #2, the EV Surface Protein Assay, uses antibody-directed click enrichment followed by immuno-PCR or RT-qPCR to quantify tumor-specific EV subpopulations. Analogous to tissue immunohistochemistry but executed in a liquid-biopsy format, this assay has shown accuracy in early detection of HCC, pancreatic ductal adenocarcinoma, and epithelial ovarian cancer and supports longitudinal monitoring in prostate and thyroid cancers. Platform #3, the EV Protease Activity Assay, extends EV analysis into functional biology by measuring enzymatic activities preserved within enriched EVs. In osteosarcoma, matrix metalloproteinase activity profiles stratified localized versus metastatic disease and tracked therapeutic response. In neurology, quantifying β-secretase activity in neuronal EVs enabled highly accurate detection of early Alzheimer's disease and correlated with cognitive performance.Together, these TCO-Tz click chemistry-enabled platforms provide a modular, robust, and clinically adaptable toolkit for noninvasive EV-based diagnostics. By uniting chemical precision with biological and clinical relevance, this framework advances the broader vision of real-time, disease-specific liquid biopsy across oncology and neurodegeneration, laying the foundation for next-generation integrated diagnostic systems.},
}

@article {pmid42134480,
year = {2026},
author = {Wu, Q and Cui, X and Liu, X and Yuan, X and Wang, P and Li, H and Xiu, R},
title = {Tetramethylpyrazine improving cerebral microcirculation in Alzheimer's Disease mice.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111936},
doi = {10.1016/j.brainresbull.2026.111936},
pmid = {42134480},
issn = {1873-2747},
abstract = {Cerebrovascular dysfunction plays a crucial role in the development and progression of Alzheimer's Disease (AD). Tetramethylpyrazine, a bioactive alkaloid monomer derived from Chinese herbal medicine Chuanxiong (Ligusticum chuanxiong), has been demonstrated to improve tissue microcirculation. However, direct in vivo monitoring of cerebral microcirculation is still challenging due to the presence and thickness of the skull. In this study, we constructed a visualized mouse cranial window and utilized photoacoustic microscopy, laser speckle imaging, and Laser Doppler flowmetry to investigate the effect of Tetramethylpyrazine on cortical microvascular function in normal mice, AD mice, and Tetramethylpyrazine-treated AD mice. Our results revealed impaired cerebral microvascular perfusion in AD mice, including significant reductions in blood flow velocity, oxygen saturation, and metabolic rate of oxygen. Tetramethylpyrazine treatment improved cortical microvascular function in AD mice, with endothelium-derived microvascular signals playing a key role in microvascular rhythmic motion. These findings suggest that Tetramethylpyrazine has the ability to enhance cortical microcirculation in AD mice through multiple mechanisms, particularly through endothelial improvement. Tetramethylpyrazine may serve as a potential candidate drug for AD treatment, and photoacoustic microscopy holds promise in the clinical observation of cortical microcirculation in AD.},
}

@article {pmid42134886,
year = {2026},
author = {Chinnathambi, S and Rangappa, N},
title = {Biosimilars: Antibody and nanobody-based therapeutic approaches towards protein misfolding diseases.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {157-195},
doi = {10.1016/bs.apcsb.2025.10.014},
pmid = {42134886},
issn = {1876-1631},
mesh = {Humans ; *Biosimilar Pharmaceuticals/therapeutic use/chemistry/pharmacology ; *Proteostasis Deficiencies/drug therapy/metabolism/pathology ; *Single-Domain Antibodies/therapeutic use ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; tau Proteins/metabolism/antagonists & inhibitors/immunology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; alpha-Synuclein/metabolism/antagonists & inhibitors ; *Parkinson Disease/drug therapy/metabolism/pathology ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, and Parkinson's disease, are characterized by progressive neuronal dysfunction and degeneration. These conditions often share pathological hallmarks such as protein misfolding, oxidative stress, neuroinflammation, and mitochondrial dysfunction. This review focuses on key pathological players like Tau and Amyloid-beta in Alzheimer's disease, highlighting their roles in microtubule destabilization, synaptic dysfunction, and neuronal death. The interplay between oxidative stress and these proteinopathies exacerbates neurodegeneration. Recent advances in therapeutic strategies are also explored, particularly the promise of biosimilars, cost-effective alternatives to biologics, targeting pathological hallmarks in neurodegenerative diseases. Biosimilars targeting Tau and Amyloid-beta in Alzheimer's disease, and alpha-synuclein in Parkinson's disease, hold the potential to improve treatment accessibility and reduce economic burdens. However, their development is still in its early stages. This review underscores the urgent need for innovative, affordable, and globally accessible therapeutic solutions to address the rising burden of neurodegenerative diseases.},
}

Humans
*Biosimilar Pharmaceuticals/therapeutic use/chemistry/pharmacology
*Proteostasis Deficiencies/drug therapy/metabolism/pathology
*Single-Domain Antibodies/therapeutic use
Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Alzheimer Disease/drug therapy/metabolism/pathology
tau Proteins/metabolism/antagonists & inhibitors/immunology
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
alpha-Synuclein/metabolism/antagonists & inhibitors
*Parkinson Disease/drug therapy/metabolism/pathology

@article {pmid42134887,
year = {2026},
author = {Chinnathambi, S},
title = {Induced-pluripotent stem cell-derived immunotherapy for Tau and Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {197-224},
doi = {10.1016/bs.apcsb.2025.10.005},
pmid = {42134887},
issn = {1876-1631},
mesh = {*Alzheimer Disease/therapy/immunology/pathology/metabolism ; Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism/immunology ; *tau Proteins/immunology/metabolism ; *Immunotherapy ; Animals ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, are characterized by progressive neuronal death and functional decline. Key pathological hallmarks of Alzheimer's disease include the deposition of aggregated amyloid-β (Aβ) proteins into extracellular plaques and the accumulation of hyperphosphorylated Tau protein into intracellular aggregates. These toxic species triggers neuroinflammation through interactions with glial cells, further exacerbating neurodegeneration. This study explores the potential of induced pluripotent stem cells (iPSCs) in disease modelling, focusing on their application in modelling Alzheimer's disease pathology and therapeutic screening. Additionally, the development of advanced 3D culture systems and organoids offers insights into human-specific Alzheimer's disease mechanisms, overcoming limitations of traditional 2D and animal models. The focus is on the role of microglial polarization in neuroinflammation and its potential therapeutic modulation, offering a promising approach for the treatment of neurodegenerative diseases.},
}

*Alzheimer Disease/therapy/immunology/pathology/metabolism
Humans
*Induced Pluripotent Stem Cells/cytology/metabolism/immunology
*tau Proteins/immunology/metabolism
*Immunotherapy
Animals

@article {pmid42135923,
year = {2026},
author = {Mia, E and Hossain, MA and Bristy, AH and Hossan, R and Asif, U and Sherwani, AK and Alshahrani, MY and Selim, S and Rakib, IH and Yana, NT and Akter, K and Hasan, MSA},
title = {Neuroprotective Properties of Litchi chinensis and Its Phytochemicals in Preclinical Models of Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {16},
number = {5},
pages = {e71474},
doi = {10.1002/brb3.71474},
pmid = {42135923},
issn = {2162-3279},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Litchi/chemistry ; Animals ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; *Phytochemicals/pharmacology ; *Plant Extracts/pharmacology ; Humans ; Rats ; Oxidative Stress/drug effects ; Mice ; Amyloid beta-Peptides/metabolism ; },
abstract = {PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. This review systematically evaluates the neuroprotective effects of Litchi chinensis and its phytochemicals against AD, focusing on modulation of Aβ accumulation, tau pathology, oxidative stress, neuroinflammation, apoptosis, and synaptic dysfunction using available preclinical evidence.

METHOD: A systematic literature search was conducted in PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar up to August 2025 using relevant keywords. Studies investigating neuroprotective effects of Litchi chinensis extracts or compounds in in vitro or in vivo AD models were included, while unrelated studies, duplicates, abstracts, and non-full-text articles were excluded.

RESULTS: Litchi chinensis extracts and phytochemicals demonstrated broad neuroprotective actions. In triple-transgenic mice, oligonol treatment (0.25-0.50 mg/mL) significantly reduced amyloid precursor protein (APP), β-secretase, and amyloid-β levels, while also decreasing tau hyperphosphorylation. Seed extracts (0.7-2.8 g/kg/day) reduced amyloid-β accumulation and neuronal injury in Sprague-Dawley rats. Anti-inflammatory effects were evident through decreased tumor necrosis factor-α, IL-1β, IL-6, and interferon gamma, alongside increased IL-4. Antioxidant defenses were enhanced via upregulation of antioxidant enzymes such as glutathione peroxidase-1 and superoxide dismutase-2, while apoptosis was suppressed by increasing Bcl-2 and reducing Bax and caspase activity. Synaptic integrity was preserved through upregulation of PSD95, synaptophysin, and serotonin receptor proteins, resulting in improved learning and memory in AD models. Additional benefits included enhanced mitochondrial and proteasomal activity, alleviation of endoplasmic reticulum (ER) stress, and induction of neurotrophic factors like insulin-like growth factor 2 and fibroblast growth factor 21.

CONCLUSION: Litchi chinensis demonstrates a multitargeted neuroprotective role, making it a promising natural therapeutic candidate for Alzheimer's management. However, as most findings are limited to preclinical models, further clinical studies are necessary to validate efficacy, ensure safety, and explore its translational potential.},
}

*Alzheimer Disease/drug therapy/metabolism
*Litchi/chemistry
Animals
*Neuroprotective Agents/pharmacology
Disease Models, Animal
*Phytochemicals/pharmacology
*Plant Extracts/pharmacology
Humans
Rats
Oxidative Stress/drug effects
Mice
Amyloid beta-Peptides/metabolism

@article {pmid42136137,
year = {2026},
author = {Bao, L and Zhao, F and Xu, W and Jiang, P and Zhang, Y and Luo, Y and Guan, W and Li, M and Chen, Q and Zhang, L and Kuang, H and Li, J and Liu, Y},
title = {Pharmacodynamics and mechanisms of triterpene components from the leaves of Astragalus mongholicus Bunge in the treatment of Alzheimer's disease.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/14786419.2026.2671969},
pmid = {42136137},
issn = {1478-6427},
abstract = {This study investigates the therapeutic potential and underlying mechanisms of triterpenoids (TR) derived from the leaves of Astragalus mongholicus Bunge for the treatment of Alzheimer's disease (AD). Eighteen triterpenoid compounds were identified in the TR fraction using UPLC-Q-TOF-MS. In the 3 × Tg-AD transgenic mouse model, the therapeutic efficacy of TR was assessed using a comprehensive approach that included the Morris water maze, histopathological analysis, transmission electron microscopy, and Western blotting. The findings revealed that TR significantly improved spatial learning and memory impairments, reduced hippocampal neuronal degeneration, and diminished the deposition of phosphorylated Tau (p-Tau) protein. Ultrastructural examination further confirmed that TR preserved mitochondrial integrity. Mechanistic studies showed that TR upregulated key mitophagy-related proteins in both PINK1/Parkin-dependent and -independent pathways. In conclusion, TR exerts neuroprotective effects by activating mitophagy through multiple pathways, highlighting its potential as a promising therapeutic candidate for AD. This study not only provides experimental evidence for the therapeutic potential of natural products targeting mitophagy in Alzheimer's disease but also expands the medicinal development value of the leaves of Astragalus mongholicus Bunge.},
}

@article {pmid42136262,
year = {2026},
author = {Khan, MA and Khan, ZA and Shoeb, F and Siddiqui, Z and Pandey, G and Fatima, G and Khan, RH and Khan, MM},
title = {Role of De Novo Lipogenesis in Neurodegeneration and Neurogenesis Disruption in Alzheimer's Disease and Treatment Perspective.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X423516260216052123},
pmid = {42136262},
issn = {1875-6190},
abstract = {Progressive neurodegeneration, decline in neurogenesis, and cognitive dysfunction alongside amyloid-β plaque and neurofibrillary tangle formation are prominent pathological features of Alzheimer's Disease (AD). Although the underlying mechanism remains unclear, evidence suggests that surplus intracellular lipids/fatty acids could be the primary mediators. In this regard, increased levels of Saturated Fatty Acids (SFAs), Monounsaturated Fatty Acids (MUFAs), their triglyceride and ceramide derivatives have been reported in the brain of patients with AD. Further, converging evidence from basic and clinical studies suggests that de novo lipogenesis could be the main source of lipid/fatty acid accumulation in the brains of patients with AD. Although elevated cholesterol has long been suggested to induce inflammation and neurodegenera-tion in AD, recent evidence suggests that the effects of SFAs and their lipid derivatives, particularly ceramides, could be more detrimental. Consequently, de novo lipogenesis inhibitors could be the potential therapeutic targets for the early intervention in AD. Intriguingly, several studies have shown that treatment with various natural or synthetic compounds, which inhibit de novo lipogenesis, effectively reduced neurodegeneration, cognitive dysfunction, and inflammation in the model animals of AD. These compounds also increased neurogenesis while reducing lipid/fatty acid accumulation, suggesting that blocking lipid/fatty acid biosynthesis by inhibiting de novo lipogenesis could be an effective strategy in treating AD. Thus, while the study discusses the effects of various FDA-approved AD drugs and selected natural and synthetic inhibitors of de novo lipogenesis on neurodegeneration and neurogenesis in model animals, the doors are open for conducting clinical trials in patients with AD.},
}

@article {pmid42136266,
year = {2026},
author = {Gupta, S and Nihal, PM and Jawaid, T and Ashesh, AM and Bhise, MR and Rawat, M and Lohidasan, S and Wal, P and Kumar, A and Kumar, D and Gasmi, A},
title = {Exploring Mitochondrial Dysfunction and Protective Therapeutic Approaches to Counteract Its Role in Alzheimer's Disease Progression.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X419571260226033536},
pmid = {42136266},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is the primary cause of dementia, characterized by a progres-sive decrease in mental abilities and the accumulation of amyloid-beta (Aβ) peptides in the brain. The combination of these peptides leads to the development of neuritic plaques and neurofibrillary tangles that disrupt neural communication and eventually lead to the loss of neurons. One of the fac-tors that are involved in the development of AD is mitochondrial dysfunction. Disrupted function-ing of mitochondria leads to the production of less energy by the cells, increased oxidative stress, and accelerates the neurodegeneration process. Neurons that carry out their mitochondrial functions normally are required to keep the balance of calcium, in a reasonable energy production, and in the survival of the cells. Mitophagy, which guarantees the clearing of damaged mitochondria, is im-paired in AD. Cholinesterase blockers and NMDA receptor blockers are currently used as treat-ments, but these are not aimed at the underlying pathophysiology of the condition. New treatment approaches that are aimed at enhancing mitochondrial health, in contrast, are viable at providing a potential to decelerate or alter mitochondrial AD progression. The goals of these approaches include enhancement of the mitophagy process, alleviation of oxidative stress, and preservation of mito-chondrial health, which may disrupt major pathological events such as Aβ aggregation and tau hy-perphosphorylation. By concentrating on the replacement of mitochondria, scientists are moving in the right direction to develop therapies that will not only help control the symptoms but also cure the disease.},
}

@article {pmid42136278,
year = {2026},
author = {Sharma, A and Mittal, V and Sharma, D and Deswal, G and Das, A and Guarve, K and Grewal, AS},
title = {Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249405308251210104405},
pmid = {42136278},
issn = {1875-6166},
abstract = {INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.

METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.

RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.

DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.

CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.},
}

@article {pmid42136282,
year = {2026},
author = {Singh, P and Bhardwaj, S and Nagarajan, K},
title = {Development and Assessment of Phytoconstituents-based Nanoemulsion as a Potent Combined Therapy for Neuroprotection in Scopolamine-induced Alzheimer's Disease Rat Model.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026450795260413103307},
pmid = {42136282},
issn = {1875-5739},
abstract = {INTRODUCTION: Nanoemulsions are increasingly recognized as effective carriers for delivering neuroprotective agents in the management of neurodegenerative conditions like Alzheimer's disease. Alzheimer's Disease (AD) is a chronic and progressive neurological disorder marked by memory impairment, cognitive dysfunction, oxidative damage, and degeneration of neurons. This study focuses on designing and evaluating a nanoemulsion-based drug delivery system combining Resveratrol and Ginkgo biloba to investigate their potential neuroprotective effects in a scopolamine- induced Alzheimer's model in Wistar rats.

METHODS: A total of nine water-in-oil nanoemulsion formulations (F1-F9) were developed using probe sonication and examined for various parameters, including droplet size, zeta potential, polydispersity index (PDI), entrapment efficiency, and in vitro drug release profiles.

RESULTS: Among these, Formulation F2, containing 25 mg of Resveratrol and 25 mg of Ginkgo biloba, showed the most favourable characteristics, including a high entrapment efficiency of 90.13%, maximum drug release of 92.33%, a particle size of 92.83 nm, and a zeta potential of 30.75 mV, suggesting good stability of the formulation. For the in vivo evaluation, rats were divided into six groups: normal control, negative control (scopolamine-treated), standard treatment group (Diazepam 2 mg/kg), and three test groups with different formulations. Behavioural studies using the Y-maze demonstrated that the Test Group 1 (treated with F2 formulation) had significantly improved spontaneous alternation behaviour, indicating enhanced cognitive performance. Biochemical analysis showed reduced malondialdehyde (MDA) levels and increased glutathione (GSH) levels, suggesting potent antioxidant activity. Additionally, histopathological examination of brain tissue revealed that the F2-treated group showed reduced neuronal damage and better preservation of hippocampal structure.

DISCUSSION: In rats treated with scopolamine, the optimized F2 nanoemulsion showed excellent physicochemical stability and markedly enhanced cognitive function. Strong antioxidant and neuroprotective effects of the combination formulation are indicated by decreased MDA levels, increased GSH levels, and intact hippocampus architecture.

CONCLUSION: The Resveratrol-Ginkgo biloba nanoemulsion (F2) successfully reduced oxidative stress and cognitive impairment, indicating its potential as a treatment for early-stage Alzheimer's disease. Additional research is needed to confirm its therapeutic application.},
}

@article {pmid42136286,
year = {2026},
author = {Tiwari, P and Kadiri, SK and Sulakhiya, K},
title = {Hyperprolactinemia and Tau Pathology: Unravelling Neuroendocrine Dysregulation for Therapeutic Targeting.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026467094260417052012},
pmid = {42136286},
issn = {1875-5739},
abstract = {BACKGROUND: Hyperprolactinemia, characterized by persistently elevated serum prolactin levels, is traditionally associated with reproductive and metabolic disturbances. Emerging evidence now implicates hyperprolactinemia in central nervous system dysfunction, particularly in the pathogenesis of neurodegenerative disorders. Chronic elevation of prolactin has been linked to tau pathology, a hallmark of Alzheimer's disease and related tauopathies, through mechanisms that promote tau hyperphosphorylation, microtubule destabilization, and neuronal compromise.

METHODOLOGY: This systematic review assesses the evidence on hyperprolactinemia and tau pathology. The overall literature search was performed in PubMed, Scopus, and Web of Science with the help of certain keywords that included prolactin, tau protein, neuroinflammation, oxidative stress, and dopaminergic signaling. The studies were narrowed down to a set of pre-established inclusion and exclusion criteria (original research, molecular and clinical data, relevance to neuropsychiatric disorders, non-English articles, reviews, animal studies that did not have a translational relevance). A clear study selection procedure was used, with independent screening and consensus-based resolution. The results generalize molecular, transcriptomic, neuroimaging, and clinical data to assess mechanistic connections and treatment prospects.

RESULTS: Neurons susceptible to tau accumulation under hyperprolactinemic states exhibit altered apoptotic signaling, impaired vesicular trafficking, and mitochondrial dysfunction. These disruptions correlate with increased neuroinflammation and oxidative stress, suggesting a mechanistic link between endocrine imbalance and tau-mediated neurotoxicity. Therapeutic agents such as dopamine agonists, selective kinase inhibitors, and prolactin receptor antagonists have the potential to restore neuroendocrine homeostasis and mitigate tau pathology.

DISCUSSION: The findings underscore hyperprolactinemia as a modifiable risk factor for cognitive decline. The neuroendocrine-tau axis represents a critical interface where hormonal dysregulation may precipitate neurodegenerative cascades. Clinical implications in the manuscript include that prolactin may serve as a biomarker of an early neurodegenerative process and that its role in the treatment approach includes dopamine agonists, prolactin receptor antagonists, and kinase inhibitors. This simplified methodology will ensure the highlights are original and have translational implications beyond mere abstract repetition.

CONCLUSION: Hyperprolactinemia-induced tau dysregulation presents novel opportunities for neuroprotective targeting. By bridging molecular mechanisms with clinical relevance, this review advocates for longitudinal studies to assess cognitive outcomes in hyperprolactinemic individuals. Emphasizing endocrine health may enhance cognitive resilience and inform future strategies for diagnosis, risk stratification, and therapeutic intervention in neurodegenerative diseases.},
}

@article {pmid42136293,
year = {2026},
author = {Ramesh, J and Jayanthi, B and Mohan, VK and Srinivasan, S and Vijayalakshmi, MK and Mohan, M},
title = {Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273444679260416064255},
pmid = {42136293},
issn = {1996-3181},
abstract = {Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.},
}

@article {pmid42136299,
year = {2026},
author = {Xia, B and Wu, S and Yu, W and Lü, Y},
title = {Research Progress on Intervention Strategies Targeting the Gut-Brain Axis in Alzheimer`s Disease.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273431295251201140053},
pmid = {42136299},
issn = {1996-3181},
abstract = {As the most common neurodegenerative disease in the world, Alzheimer's Disease (AD) is characterized by a complex pathogenesis and a lack of effective treatments. In recent years, breakthroughs in the Gut-Brain Axis (GBA) theory have provided a new direction for AD intervention. Studies have shown that AD patients commonly exhibit gut dysbiosis, accompanied by decreased Short-Chain Fatty Acid (SCFA) levels, endotoxin leakage, and increased systemic inflammation, which accelerate cognitive decline via neuroinflammation, Aβ deposition, and synaptic dysfunction. Based on this, intervention strategies targeting the GBA have emerged as a focus of research for slowing down the pathological process of AD. In this study, we systematically summarize the mechanisms linking gut microbiota dysbiosis to AD pathology. This includes the roles of metabolites (e.g., SCFA, LPS, and TMAO) in modulating neuroinflammation and Blood-Brain Barrier (BBB) permeability, as well as the critical involvement of vagal nerve pathways in gut-brain signaling. We further explored the potential of probiotics to improve cognitive function by restoring microbial homeostasis, enhancing anti-inflammatory effects, and elevating neurotrophic factor levels; dietary interventions (e.g., the Mediterranean and MIND diets) to reduce AD risk by modulating microbial composition and metabolic activity; and Fecal Microbiota Transplantation (FMT) to reduce Aβ plaque deposition and mitigate neuroinflammation. Despite promising findings, challenges persist, including discrepancies between animal models and human subjects, individual variability in microbiota composition, and an incomplete understanding of underlying mechanisms. In the future, it will be necessary to combine multiple technologies to develop personalized intervention protocols and optimize clinical translation processes, providing a theoretical basis for the precise treatment of AD.},
}

@article {pmid42136342,
year = {2026},
author = {Liu, CW and Shan, ZX and Li, WJ and Qu, QW and Hou, XQ},
title = {Potential Therapeutic Effects and Mechanisms of Estrogen on Diabetes, Alzheimer's Disease,and Their Comorbidity:A Review.},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {48},
number = {2},
pages = {328-337},
doi = {10.3881/j.issn.1000-503X.16649},
pmid = {42136342},
issn = {1000-503X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/epidemiology ; *Estrogens/therapeutic use ; *Diabetes Mellitus/drug therapy/epidemiology ; Comorbidity ; },
abstract = {Estrogen is a lipid-soluble steroid hormone and one of the most important female sex hormones.It mainly functions by interacting with estrogen receptors,maintaining normal physiological and pathophysiological functions of the body,and playing a crucial role in regulating blood glucose homeostasis,metabolism,and physiological processes associated with brain learning and memory.Recent studies have shown that estrogen has potential therapeutic effects on diabetes,cognitive impairment and other diseases.It will provide new ideas and treatment strategies for diabetes,Alzheimer's disease,and their comorbidity by regulating the activity of estrogen and the interaction with estrogen receptors to modulate related pathological and physiological processes.This article reviews the latest research progress in the relationship between estrogen and these diseases,providing a new perspective and prospect for the prevention and treatment of diabetes,Alzheimer's disease,and their comorbidity.},
}

Humans
*Alzheimer Disease/drug therapy/epidemiology
*Estrogens/therapeutic use
*Diabetes Mellitus/drug therapy/epidemiology
Comorbidity

@article {pmid42136344,
year = {2026},
author = {Zhang, XT and Chen, SS and Liu, YW and Huang, HR and Yu, Y},
title = {Role of Brain Insulin Resistance in the Pathogenesis of Alzheimer's Disease.},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {48},
number = {2},
pages = {347-354},
doi = {10.3881/j.issn.1000-503X.16614},
pmid = {42136344},
issn = {1000-503X},
mesh = {*Alzheimer Disease/metabolism/etiology/physiopathology/pathology ; *Insulin Resistance ; Humans ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common type of dementia,in which brain insulin resistance (BIR) plays a key role.BIR affects the response of brain cells to insulin and is associated with cognitive decline and pathological features of AD.This study explores the role of BIR in the pathogenesis of AD and evaluates potential treatment strategies,aiming to provide new directions for the prevention and treatment of AD.},
}

*Alzheimer Disease/metabolism/etiology/physiopathology/pathology
*Insulin Resistance
Humans
*Brain/metabolism

@article {pmid42136471,
year = {2026},
author = {Sharma, S and Thakur, A and Paliwal, D and Mondal, R and Saini, S and Sahu, R and Kaushik, N and Tiwari, H},
title = {Exploring the Therapeutic Potential of Coumarin Scaffolds in Alzheimer's Disease: A Comprehensive Review.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575443995260406045449},
pmid = {42136471},
issn = {1875-5607},
abstract = {Alzheimer's disease is a progressive and debilitating form of neurological disorder that affects millions of people across the globe. Alzheimer's disease is essentially defined by the presence of cognitive decline, memory impairments, and behavioral symptoms, and it is also defined by pathological hallmarks such as amyloid plaques, Tau protein inclusions, oxidative stress, & neuroinflammation. However, despite the vast progress made in the field of neuroscience and pharmacology, there is no permanent treatment available for Alzheimer's disease, and the existing treatments are only symptomatic in nature. This has led to the search for new innovative therapeutic approaches based on small molecules with multifunctional pharmacological properties. Among different molecules, Coumarin derivatives have been identified as promising therapeutic agents owing to their high structural diversity and potent ability to bind key molecular targets involved in AD pathogenesis. Coumarin derivatives have been found to have strong potential for modulating oxidative stress, inhibitng cholinesterase, reducing neuroinflammation, and interfering with amyloid-beta aggregation. Recent advancements in the synthesis and design of coumarin derivatives have shown that slight modifications in their structure can yieldsubstantial improvements in their efficacy and selectivity in the treatment of Alzheimer's disease. For coumarin derivatives to be used in the treatment of Alzheimer's disease, they need first to be able to cross the blood-brain barrier. To overcome this limitation, scientists have been working to improve lipophilicity, optimize molecular size and polarity, and design prodrugs. This review provides an updated account of the use of coumarin derivatives in the treatment of Alzheimer's disease. It focuses on their neuroprotective and, symptommodifying effects, and their use in dealing with the multifactorial nature of the disease. Moreover, this paper aims to give recent research findings and discuss the structure-activity relationships of these compounds. The knowledge gained from this review is expected to motivate further research endeavors in the development of stronger and more specific AD drugs.},
}

@article {pmid42136472,
year = {2026},
author = {Shrivastava, N and Husain, A and Haider, K},
title = {Substituted Benzofurans as Potent Anticancer Agents: Advances, Molecular Docking, and SAR Studies.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575435772260422071930},
pmid = {42136472},
issn = {1875-5607},
abstract = {Benzofuran, an oxygen-containing fused heterocyclic aromatic compound, occurs naturally as a secondary metabolite from various plant sources like Rutaceae, Asteraceae, Cyperaceae, and Liliaceae. The derivatives of benzofuran possess a wide range of biological activities, including anticancer, anti-inflammatory, antioxidant, antibiotic, analgesic, anti-Alzheimer's, and immunosuppressive effects. Various synthetic methods are currently used to prepare various benzofuran derivatives. Its therapeutic significance is highlighted by the presence of the benzofuran core in several FDA-approved drugs. Due to the development of resistance in existing anticancer therapies, there is an urgent need for novel, effective, and safe therapeutic approaches. Many heterocyclic moieties and their structural hybrids have been explored for their potential biological activity and have attracted considerable attention as anticancer agents. Substituted benzofuran derivatives are emerging as lead candidates to meet the global challenges of cancer and its available treatment. Benzofuran has the chemical formula C8H6O. Structurally, it consists of a fused ring system: a benzene ring fused to a five-membered furan ring (with one oxygen). Both benzene and furan contribute to its aromatic character. Benzofuran heterocycle plays an important role in drug design and drug discovery due to its versatile nature. The current review summarizes the recent progress in the design, development, drug discovery, and pharmacological actions of benzofuran derivatives as anticancer agents; their molecular docking studies; and structure-activity relationships reported over the past five to six years, emphasizing fused heterocyclic analogues and their prospects to develop as lead molecules. A thorough understanding of the structure-activity relationship will provide a valuable framework for novel drug discovery and design.},
}

@article {pmid42137472,
year = {2026},
author = {Al-Karmalawy, AA and Attia, MI and Alnajjar, R and El-Shiekh, RA and Al Khatib, AO and Yousef, TA and Abdel-Sattar, E},
title = {Discovery of Caralluma-derived pregnane glycosides as potent and selective cholinesterase inhibitors: integrated in silico and in vitro evaluation.},
journal = {RSC advances},
volume = {16},
number = {27},
pages = {24903-24915},
pmid = {42137472},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is the fourth leading cause of death among elderly people worldwide. It has a complex pathogenesis, making multitarget-directed ligands (MTDLs) a key therapeutic strategy. This study evaluated pregnane glycosides isolated from Caralluma species (Apocynaceae) as potential cholinesterase inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes for AD treatment. In silico molecular docking against AChE (PDB: 4EY7) and BuChE (PDB: 8CGO) identified caratuberside E and awdelioside B as top AChE binders (-11.09 and -11.49 kcal mol[-1], outperforming the cocrystal inhibitor at -9.52 kcal mol[-1]). For BuChE, caratuberside G and penicilloside C showed superior scores (-10.94 and -11.55 kcal mol[-1] vs. -8.89 kcal mol[-1] for the cocrystal). These results were validated by 200 ns molecular dynamics simulations (stable RMSD values) and MM-GBSA binding free-energy calculations, confirming strong interactions and favourable energetics. In vitro assays (using donepezil as reference) demonstrated potent inhibition: caratuberside E was most active against AChE (IC50 = 0.69 ± 0.07 µM), followed by awdelioside B (IC50 = 18.99 ± 0.06 µM); caratuberside G (IC50 = 1.59 ± 0.16 µM) and penicilloside C (IC50 = 12.38 ± 0.51 µM) excelled against BuChE. Collectively, these pregnane glycosides from Caralluma show promise as selective cholinesterase inhibitors and potential MTDLs for AD therapy.},
}

@article {pmid41928210,
year = {2026},
author = {Leelahavarong, P and Prawjaeng, J and Angkab, P and Wongkom, N and Scheltens, P and Srinonprasert, V and Senanarong, V},
title = {Cost-utility analysis of cerebrospinal fluid versus blood biomarkers for early detection of Alzheimer's disease and mild cognitive impairment in Thailand: a modeling study.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {41928210},
issn = {1472-6963},
abstract = {OBJECTIVE: To evaluate the cost-utility of cerebrospinal fluid (CSF) and blood-based amyloid beta biomarkers for early detection of Alzheimer’s disease and mild cognitive impairment among older Thai adults at high risk of dementia.

METHODS: We constructed a decision tree with Markov models from a societal perspective, using a 1-year cycle over a lifetime horizon and applying a 3% annual discount. Amyloid beta (Aβ)1–42 was used for CSF, while Aβ40 and Aβ42 were used for blood. Sensitivity and specificity data were primarily derived from Thai patients at Siriraj Hospital, and nonpharmacological treatment efficacy was obtained from the FINGER study. Epidemiological data, transition probabilities, and costs were collected from the literature and Siriraj Hospital; direct nonmedical costs and utility values were also obtained from Siriraj. We calculated lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs), evaluating cost-effectiveness against THB160,000 (USD4,370) per QALY. Parameter uncertainty was explored via sensitivity analyses. This is non-clinical trail study.

RESULTS: Compared with no testing, the CSF strategy yielded 0.011 additional life-years and 0.019 additional QALYs for an extra cost of THB2,589 (USD71), resulting in an ICER of THB132,961 (USD3,632) per QALY. Blood-based testing provided 0.009 additional life-years and 0.017 QALYs for an extra cost of THB15,467 (USD422), leading to an ICER of THB907,057 (USD24,776) per QALY.

CONCLUSIONS: CSF biomarker testing is cost-effective in Thailand, whereas blood-based biomarkers are not. Reducing the cost of Simoa (the technology used to measure blood biomarkers) by approximately 83% would improve the cost-effectiveness of blood-based biomarkers. Future research should enhance blood biomarker accuracy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12913-026-14405-5.},
}

@article {pmid42125963,
year = {2026},
author = {Juday, TR and Holub, A and Mattke, S and Betts, KA and Kitchen, SA and Liu, H and Frech, FH and Khachaturian, AS},
title = {Community-Based Physician Attitudes Related to the Diagnosis and Treatment of Early Alzheimer's Disease in the United States.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261433309},
doi = {10.1177/15333175261433309},
pmid = {42125963},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; United States ; Male ; Female ; *Attitude of Health Personnel ; *Neurologists/psychology ; *Cognitive Dysfunction/diagnosis/therapy ; *Physicians, Primary Care/psychology ; Middle Aged ; Early Diagnosis ; },
abstract = {The increasing incidence of Alzheimer's disease (AD) coupled with emerging diagnostics and treatments underscores the need for early detection of AD, yet identifying these individuals remains challenging. This US study sought to examine community-based physician attitudes regarding diagnosis and treatment of early AD (mild cognitive impairment [MCI] due to AD and mild AD). A total of 177 primary care physicians (PCPs) and 147 neurologists recruited through a national physician panel were surveyed about early AD diagnostic and treatment processes, and self-confidence in identifying and managing the condition. Physicians identified patient and family/caregiver involvement as critical in triggering the diagnostic process. Patterns of use of neurocognitive assessments, structural imaging tests, and AD-specific biomarkers varied between PCPs and neurologists. Confidence diagnosing and managing early AD was a concern across specialties, although was greater among PCPs. Programs promoting awareness of early AD symptoms, and emerging technologies and treatments are critical to timely management.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
United States
Male
Female
*Attitude of Health Personnel
*Neurologists/psychology
*Cognitive Dysfunction/diagnosis/therapy
*Physicians, Primary Care/psychology
Middle Aged
Early Diagnosis

@article {pmid42126808,
year = {2026},
author = {Taylor, TL and Tuke, J and Fernandez, EJ and Hazel, SJ},
title = {Group training classes for dogs with canine cognitive dysfunction: effects on sleep, activity, and caregiver burden.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42126808},
issn = {2509-2723},
abstract = {Canine Cognitive Dysfunction (CCD) is a progressive neurodegenerative condition of ageing dogs, sharing pathological and clinical features with Alzheimer's disease. Despite the growing prevalence of CCD, non-pharmacological interventions for affected companion animals remain underexplored. This study evaluated the effects of structured group training classes on signs of CCD, sleep, daily activity, and caregiver burden. Forty-two dogs (≥ 8 years) with mild to moderate CCD were enrolled in either a scent-based (S; n = 21) or physical structured training (PST; n = 21) program. Each dog completed five consecutive weekly sessions, with outcomes assessed through the Canine Dementia Scale (CADES), accelerometry (FitBark), and validated caregiver burden measures at baseline, treatment, and post-treatment. CCD scores remained stable across all phases, suggesting no measurable cognitive changes. However, a significant interaction between training type and treatment phase was observed for sleep: dogs in the PST group demonstrated improved Fitbark sleep scores over time, while those in the S group declined. Daily activity followed expected bimodal patterns, with scent-trained dogs exhibiting reductions in morning and evening activity peaks. Caregiver burden decreased significantly across time in both groups, and caregivers reported high satisfaction with class participation, citing enhanced confidence and social support. These findings indicate that while structured training did not alter CCD severity scores, PST was associated with a small improvement in sleep, S was associated with reduced activity, and participation in both classes was linked to reduced caregiver burden. Further research is needed to confirm these changes and determine their effect on dog and human wellbeing. Group training classes may represent an accessible, welfare-focused intervention for managing CCD in companion dogs.},
}

@article {pmid42127455,
year = {2026},
author = {Tzieras, I and Manolopoulos, A and Tweedie, D and Luo, W and Maccecchini, M and Egan, JM and Greig, NH and Kapogiannis, D},
title = {A phase 1, safety, tolerability, and pharmacokinetics study of bisnorcymserine, a highly selective inhibitor of butyrylcholinesterase.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {3},
pages = {e00918},
doi = {10.1016/j.neurot.2026.e00918},
pmid = {42127455},
issn = {1878-7479},
abstract = {Cholinergic deficiency is a hallmark neurotransmitter abnormality in Alzheimer's disease (AD) that has traditionally been addressed with cholinesterase inhibitors. In severe AD, butyrylcholinesterase (BuChE) becomes the dominant cholinesterase, suggesting a potential therapeutic target. (-)-N1,N8-bisnorcymserine tartrate (BNC) is a selective BuChE inhibitor designed to address this unmet need. We conducted a phase I, single-center, randomized, double-blind, placebo-controlled, ascending single oral dose clinical trial to evaluate the safety, tolerability, and pharmacokinetics of BNC in 30 healthy volunteers. There were no adverse events (AEs) grade 2 or above or any serious adverse events (SAEs). Most events were mild and self-limited, the most common being asymptomatic bradycardia and headache. The mean AUClast (SD) was 120.98 h∗ng/mL (74.30) for the 40 mg dose, 148.20 h∗ng/mL (99.43) for the 80 mg dose, and 196.33 h∗ng/mL (91.74) for the 120 mg dose. Accordingly, median tmax (range) and mean Cmax (SD) were 1.8 (1.0-5.0) hr and 13.94 (7.64) ng/mL for the 40 mg dose, 1.8 (1.5-5.0) hr and 18.54 (6.44) ng/mL for the 80 mg dose, and 2 (1.0-4.5) hr and 20.93 (5.00) ng/mL for the 120 mg dose. The mean half-life of BNC ranged from 5.5 to 7 h. BNC was safe and well tolerated when administered as a single oral dose of up to 120 mg. This first-in-human, phase I study permits further investigation of this drug as a potential symptomatic treatment for AD. ClinicalTrials.gov, NCT01747213.},
}

@article {pmid42128444,
year = {2026},
author = {Atri, A and Apostolova, LG and Iwata, A and Wessels, AM and Atkins, A and Lu, M and Ye, W and Ryan, S and Doty, EG},
title = {Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {3},
pages = {e200621},
doi = {10.1212/CPJ.0000000000200621},
pmid = {42128444},
issn = {2163-0933},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Aged ; *Cognitive Dysfunction/drug therapy ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Aged, 80 and over ; Disease Progression ; Activities of Daily Living ; *Outcome Assessment, Health Care ; },
abstract = {BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers.

METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score.

RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005).

DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making.

ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.},
}

Humans
*Alzheimer Disease/drug therapy
Aged
*Cognitive Dysfunction/drug therapy
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Aged, 80 and over
Disease Progression
Activities of Daily Living
*Outcome Assessment, Health Care

@article {pmid42129577,
year = {2026},
author = {Stark, M and Wagner, M and Kuhn, E and Roeske, S and Amthauer, H and Bartels, C and Boecker, H and Brosseron, F and Buchert, R and Buerger, K and Daamen, M and Drzezga, A and Düzel, E and Ersözlü, E and Essler, M and Ewers, M and Fliessbach, K and Glanz, W and Hellmann-Regen, J and Incesoy, EI and Janowitz, D and Kafali, K and Kilimann, I and Krause, BJ and Kronmüller, M and Laske, C and Maier, F and Maurer, A and Michely, J and Perneczky, R and Peters, O and Preis, L and Priller, J and Rauchmann, BS and Reimold, M and Rominger, A and Schmid, M and Schneider, A and Sodenkamp, S and Spottke, A and Spruth, EJ and Teipel, S and Wiltfang, J and , and Jessen, F and Kleineidam, L},
title = {Minor neuropsychological deficits and stage 2 of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71458},
pmid = {42129577},
issn = {1552-5279},
support = {//Gemeinnützige Hertie-Stiftung/ ; BN012//Deutsches Zentrum für Neurodegenerative Erkrankungen/ ; //Life Molecular Imaging/ ; U01AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//U.S. Department of Defense/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //Biogen/ ; //Bristol-Myers Squibb/ ; //CereSpir, Inc./ ; //Cogstate/ ; //Eisai/ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun Medizinische Labordiagnostika/ ; //F. Hoffmann-La Roche/ ; //Genentech/ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development, LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Transition Therapeutics/ ; /CAPMC/CIHR/Canada ; U24 AG072122/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; Female ; Aged ; Neuropsychological Tests/statistics & numerical data ; Male ; *Cognitive Dysfunction/diagnosis ; Longitudinal Studies ; Biomarkers ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Subtle symptoms, like subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD), can improve the risk stratification in preclinical Alzheimer´s disease (AD) but their importance is insufficiently elaborated.

METHODS: We pooled data from cognitively normal individuals participating in three longitudinal cohort studies (N = 13,192, 8,359[63.3%] female, mean [SD] age 71.0[8.4]).

RESULTS: Compared to participants without SCD and MNPD (SCD-/MNPD-), SCD-/MNPD+, SCD+/MNPD-, and SCD+/MNPD+ participants had an increased risk for mild cognitive impairment (MCI) and dementia, including in amyloid-positive individuals. Focusing on SCD+/MNPD+ participants triples the positive predictive value of amyloid biomarker testing for the 5-year prediction of MCI and reduces the required samples size for trials in preclinical AD to one fourth, compared to considering all cognitively normal participants regardless of subtle symptoms.

DISCUSSION: SCD and MNPD offer a powerful approach for risk stratification in preclinical AD, which can improve clinical trial designs, risk counseling, and future case identifications for early treatment.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
Female
Aged
Neuropsychological Tests/statistics & numerical data
Male
*Cognitive Dysfunction/diagnosis
Longitudinal Studies
Biomarkers
Aged, 80 and over

@article {pmid42130250,
year = {2026},
author = {Akar, S and Alvur, O and Evyapan, G and Ozdem, B and Porsuk Doru, I},
title = {Escin Attenuates Amyloid Beta 1-42-Induced Oxidative Stress, Apoptosis, and Neuroinflammation in Neuron-Like SH-SY5Y Cells.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70903},
doi = {10.1002/jbt.70903},
pmid = {42130250},
issn = {1099-0461},
support = {TSA-2023-10713//Van Yuzuncu Yıl University Research Fund/ ; },
mesh = {*Amyloid beta-Peptides/toxicity ; Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Peptide Fragments/toxicity ; Cell Line, Tumor ; *Neurons/metabolism/pathology/drug effects ; *Escin/pharmacology ; Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology ; *Neuroinflammatory Diseases/metabolism/pathology/drug therapy ; Cell Survival/drug effects ; Alzheimer Disease/metabolism/drug therapy/pathology ; NF-kappa B/metabolism ; Inflammation/metabolism ; },
abstract = {The pathogenesis of Alzheimer's disease (AD) involves amyloid beta (Aβ)-induced oxidative stress, apoptotic cell death, and neuroinflammation, contributing to neuronal dysfunction. In our study, a differentiation protocol using retinoic acid was applied to SH-SY5Y cells to generate a neuron-like phenotype, and the neuroprotective efficacy of Escin was investigated by inducing Aβ1-42-mediated cytotoxicity. The experimental protocol involved an initial treatment with 2 µM Escin prior to Aβ1-42 application. Cell viability, intracellular reactive oxygen species (ROS), apoptosis, and inflammatory mediator expression (NF-κB, TNF-α, IL-1β) were assessed by MTT assay, flow cytometry with DCFH-DA, flow cytometry with Annexin V-FITC/7-AAD staining, and RT-qPCR, respectively. In our results, Aβ1-42 exposure was found to significantly reduce cell viability and increase ROS production. Additionally, it was observed to enhance apoptotic cell death and increase pro-inflammatory gene expression. Escin pretreatment was found to significantly mitigate these effects by reducing oxidative stress, apoptosis, and NF-κB-mediated inflammatory signaling. Furthermore, galantamine (10 µM), an approved AD treatment agent, was used as a positive control to compare the effects of Escin and confirmed the experimental model by exhibiting protective effects. In conclusion, these findings demonstrate that Escin is a promising neuroprotective agent and warrant further investigation into its potential to mitigate Aβ-related neuronal damage in AD.},
}

*Amyloid beta-Peptides/toxicity
Humans
*Oxidative Stress/drug effects
*Apoptosis/drug effects
*Peptide Fragments/toxicity
Cell Line, Tumor
*Neurons/metabolism/pathology/drug effects
*Escin/pharmacology
Reactive Oxygen Species/metabolism
*Neuroprotective Agents/pharmacology
*Neuroinflammatory Diseases/metabolism/pathology/drug therapy
Cell Survival/drug effects
Alzheimer Disease/metabolism/drug therapy/pathology
NF-kappa B/metabolism
Inflammation/metabolism

@article {pmid42130609,
year = {2026},
author = {Gobbi, S and Silvestri, E and Tonietto, M and Klein, G and van den Heuvel, M and Magon, S},
title = {Functional connectome metrics reveal distinct prognostic subtypes in two Phase 3 gantenerumab trials.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70259},
pmid = {42130609},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity poses significant challenges for drug development, identification of individuals at risk, and treatment response prediction. Scientists have leveraged graph theory and resting-state functional magnetic resonance imaging (rs-fMRI) to successfully stratify people with AD. Still, the prognostic value of rs-fMRI graph metrics in AD clinical trials remains unclear.

METHODS: We analyzed rs-fMRI from participants in amyloid-lowering clinical trials. Four graph metrics-global efficiency, clustering coefficient, modularity, and shortest path length-were computed and baseline clusters defined using unsupervised k‑means. We investigated the baseline connectome of each cluster to assess the level of network dysfunction and impairment (i.e., loss of global integration, resulting in disrupted communication between brain regions and reduced global efficiency). These clusters were related to a 116-week change in cognition and brain volume using covariate-adjusted mixed-effects models.

RESULTS: Three clusters emerged with distinct functional connectome efficiency, demographic, and AD-related biomarkers profiles. These baseline differences led to significant variations in disease progression. The most impaired‑connectome cluster declined fastest, whereas the most integrated declined slowest.

DISCUSSION: rs-fMRI graph metrics might effectively stratify participants with AD in clinical trials and serve as potential prognostic biomarkers.},
}

@article {pmid42130762,
year = {2026},
author = {Liu, XY and Yan, YZ and Jiang, AJ and Tan, SJ and Fang, YY and Zeng, P},
title = {Integrating network pharmacology and experimental validation strategies to investigate the mechanisms and key flavonoids in medicinal and edible citrus plants against Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1801263},
pmid = {42130762},
issn = {1663-4365},
abstract = {INTRODUCTION: Due to the complexity of the Alzheimer's disease (AD) pathophysiological processes, there is currently a lack of effective therapeutic drugs. The medicinal and edible substances have multiple advantages in treating AD, but their specific components and mechanisms remain unclear. This study aims to investigate the potential mechanisms of flavonoids in medicinal and edible citrus plants in treating AD and their key phytochemicals.

METHODS: We collected flavonoids identified by UHPLC-Q-TOF-MS/MS in citrus plants from the literatures and evaluate their pharmacological and toxicological parameters. We obtained and systematically analyzed the action targets of the flavonoids of citrus plants and screened the targets related to AD key pathophysiological processes and the corresponding phytochemicals. The results of network pharmacological analysis were further validated through molecular docking, GEO database, and BV2 microglial cells.

RESULTS: A total of 51 flavonoids in medicinal and edible citrus plants were identified, which exhibit favorable pharmacological properties and safety profiles. Multiple flavonoid compounds such as isoquercitrin, astragalin, cynaroside, troxerutin and lonicerin serve as potential acetylcholinesterase inhibitors for the symptomatic treatment of AD. The study identified 45 flavonoids in citrus plants that correspond to 304 AD-related targets, which are involved in multiple pathophysiological processes. Quercetin, nobiletin, hesperidin, apigenin, HTMF, tangeretin and hesperetin have been identified as the key flavonoids of citrus plants that regulate the pathogenesis of AD in a multitargeted manner. The flavonoids of citrus plants primarily regulate the core targets AKT1, TNF, IL6, TP53, IL1B, STAT3, INS, JUN, CASP3 and CTNNB1. Targeting ferroptosis is one of the mechanisms by which citrus plants to ameliorate AD. In vitro experiments also demonstrated that hesperidin and naringin alleviated LPS-induced pro-inflammatory activation of BV2 cells.

CONCLUSION: The various citrus plants flavonoids examined in this study exhibit significant potential for clinical translation, particularly in the early prevention and adjuvant treatment of AD.},
}

@article {pmid42131436,
year = {2026},
author = {Gusmão, LA and Metzke, A and Deau, E and Meijer, L and Tedesco, AC and Köster, RW},
title = {Nitrogen-Doped Graphene Quantum Dots Conjugated to Leucettinib-21 Rescue Differentiating Zebrafish Purkinje Cells by Inhibiting Dyrk1A Kinase.},
journal = {ACS applied nano materials},
volume = {9},
number = {18},
pages = {8023-8038},
pmid = {42131436},
issn = {2574-0970},
abstract = {A major challenge in treating neurological diseases is the transport of compounds across the blood-brain barrier. Herein, we report the synthesis and characterization of nitrogen-doped graphene quantum dots (GQDs) that exhibit high tolerance in zebrafish larvae at high concentrations. In contrast to classical semiconductor quantum dots, vascular microinjection of these fluorescent carbon-based nanomaterials results in rapid tissue distribution and efficient neuronal internalization within the brain, highlighting their potential as nanocarriers for central nervous system delivery. Vascular microinjections of these quantum dots conjugated with the high-affinity Dyrk1A kinase inhibitor Leucettinib-21 (LCTB21) at nanomolar concentrations rescued cell-autonomous dendrite deficiencies in cerebellar Purkinje cells overexpressing human Dyrk1a. LCTB21 concentrations were significantly lower than those of the inhibitor alone. Dyrk1A activity is responsible for neurological defects in Down syndrome and acts as a priming kinase for Alzheimer's disease-associated proteins Tau and APP. Thus, efficient nanodelivery of Dyrk1A inhibitors across the blood-brain barrier improves therapeutic options while minimizing the treatment dose and potential side effects.},
}

@article {pmid42133413,
year = {2026},
author = {Berezutsky, MA and Andronova, TA and Belonogova, YV and Durnova, NA},
title = {[Acteoside: neurobiological activity spectrum, potential in the treatment of age-associated neurodegenerative diseases].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4},
pages = {41-47},
doi = {10.17116/jnevro202612604141},
pmid = {42133413},
issn = {1997-7298},
mesh = {Humans ; *Glucosides/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy/metabolism ; *Phenols/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Microglia/drug effects ; *Neurodegenerative Diseases/drug therapy ; Polyphenols ; },
abstract = {Acteoside (verbascoside, kusaginin) is a phenylethanoid glycoside, which is found in more than 200 species of plants and is characterized by a wide range of pharmacological activity. The results of studies on the neurobiological effects of acteoside, which can be used in the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD), were summarized and analyzed. The PubMed, Scopus, Google Scholar, and e-Library databases were searched for the following keywords: «acteoside», «Alzheimer's disease», «Parkinson's disease», «pathological activation of microglia», «neurotrophic effect», «endoplasmic reticulum stress», «protection of neurons from beta-amyloid», «inhibition of tau protein hyperphosphorylation», «death of dopaminergic neurons», «aggregation of α-synuclein», «cognitive and motor impairment». Experimental studies have shown the ability of acteoside to inhibit pathological activation of microglia, exert a neurotrophic effect, inhibit endoplasmic reticulum stress, protect neurons from beta-amyloid, inhibit tau-protein hyperphosphorylation, reduce intracellular Ca[2+] mobilization dysfunction, protect neurons from glutamate-induced neurotoxicity, prevent dopaminergic neuron death, reduce α-synuclein aggregation, and attenuate cognitive and motor impairments. This compound has good prospects for chemical modification, as its structure features several reactive sites. In the future, acteoside may be used as a multi-purpose complex therapy for AD and PD.},
}

Humans
*Glucosides/therapeutic use/pharmacology
*Parkinson Disease/drug therapy/metabolism
*Phenols/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Endoplasmic Reticulum Stress/drug effects
Animals
Amyloid beta-Peptides/metabolism
Microglia/drug effects
*Neurodegenerative Diseases/drug therapy
Polyphenols

@article {pmid42133414,
year = {2026},
author = {Shavlovskaya, OA},
title = {[Choline alfoscerate in the treatment of cognitive impairment].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4},
pages = {48-55},
doi = {10.17116/jnevro202612604148},
pmid = {42133414},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/drug therapy ; *Glycerylphosphorylcholine/therapeutic use/administration & dosage ; Alzheimer Disease/drug therapy ; Administration, Oral ; Injections, Intramuscular ; },
abstract = {Multiple randomized controlled trials (RCTs), systematic reviews, meta-analyses, and multidisciplinary studies in both hospital and outpatient settings have demonstrated the high efficacy and safety of choline alfoscerate (CA) therapy for patients with mild and moderate cognitive impairment (MCI), amnestic cognitive impairment, predementia cognitive impairment in Alzheimer's disease (AD), elderly individuals, and first-degree relatives of patients with AD as preventive therapy. The Russian CA drug Cereton is available in several formulations, including solutions for intravenous and intramuscular injection, capsules, and an oral solution, enabling individualized treatment approaches. In hospital settings, injection therapy with Cereton is administered for 10 days, followed by an oral course lasting up to 60 days. The duration and dosage of Cereton oral solution and capsules are determined by patient age and clinical condition. The oral solution is approved for use in children from 6 years of age, and the capsules are approved for use in children from 11 years of age, with treatment courses lasting up to 60 days. Cereton therapy consists of two stages: initial intravenous or intramuscular administration, followed by oral administration of capsules or the oral solution. The drug is generally well-tolerated, with adverse events being infrequent and minor.},
}

Humans
*Cognitive Dysfunction/drug therapy
*Glycerylphosphorylcholine/therapeutic use/administration & dosage
Alzheimer Disease/drug therapy
Administration, Oral
Injections, Intramuscular

@article {pmid42133852,
year = {2026},
author = {Juni, JE and Burns, JM and Salat, DH and Hill, D and Tally, S and Martin, JS and Devous, MD and Moriarty, PM},
title = {Treatment of Clinically Diagnosed Alzheimer's Disease by External Counterpulsation A Randomized Clinical Trial.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261451918},
doi = {10.1177/15333175261451918},
pmid = {42133852},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/therapy ; Female ; Male ; Aged ; *Counterpulsation/methods ; Aged, 80 and over ; *Cognitive Dysfunction/therapy ; Treatment Outcome ; Activities of Daily Living ; },
abstract = {ObjectiveTo assess external counterpulsation (ECP) effects on cognitive and functional decline in early AD.MethodsThis 12-month, multicenter, blinded, randomized, sham-controlled trial enrolled 190 patients with early AD (MCI due to AD or mild AD per NIA-AA clinical criteria). Participants received either full-pressure ECP (150-300 mmHg) or sham (25 mmHg): 3-5 weekly one-hour sessions for 35 treatments, then twice-weekly through six months. Assessments occurred at baseline and weeks 6, 12, 18, 24, 36, and 52. Primary endpoints included ADCS-ADL, ADAS-cog-14, and VADAS-cog.ResultsFull-pressure ECP significantly improved ADCS-ADL scores versus sham (mean change 2.57 vs. -0.49; p=0.036) and VADAS-cog scores (9.95 vs. 5.22; p=0.005) at 12-24 weeks. Benefits persisted through 52 weeks despite treatment cessation at 6 months. No serious device-related adverse events occurred.ConclusionsFull-pressure ECP therapy significantly improved cognition and ADL compared to sham treatment in early AD. ECP represents a novel therapeutic approach warranting further investigation.},
}

Humans
*Alzheimer Disease/therapy
Female
Male
Aged
*Counterpulsation/methods
Aged, 80 and over
*Cognitive Dysfunction/therapy
Treatment Outcome
Activities of Daily Living

@article {pmid41918005,
year = {2026},
author = {Singh, S and Sharma, Y and Bhardwaj, P and Kothari, D and Chhikara, A and Gupta, V and Kumar, D and Choudhary, N and Kondaveeti, SB},
title = {Next generation preventive neurology: how artificial intelligence and machine learning are reshaping Alzheimer's disease research.},
journal = {Behavioral and brain functions : BBF},
volume = {22},
number = {1},
pages = {},
pmid = {41918005},
issn = {1744-9081},
abstract = {UNLABELLED: A neurological condition that worsens over time, Alzheimer’s disease (AD) is typified by memory loss, cognitive decline, and functional degradation. Traditional diagnostic techniques such as neuroimaging, cerebrospinal fluid biomarkers, and neuropsychological testing are often intrusive, costly, or insensitive in the early stages. Recent years have seen the emergence of AI and ML as game-changing technologies for AD risk assessment, early detection, and customized prevention. Using sophisticated models such as deep learning, convolutional neural networks (CNNs), and graph-based algorithms, AI-driven methods achieve high performance: CNNs, for example, have reached diagnostic accuracies of 94–99% for early AD and mild cognitive impairment using multimodal MRI and PET data. However, most reported performance metrics are derived from retrospective analyses and internal validation cohorts, with limited external validation across diverse populations. These methods include multimodal data integration from neuroimaging, genetics, and clinical records. Years before symptoms appear, AI-based frameworks can predict disease progression, identify modifiable risk factors, and guide individualized treatment plans. Future developments in federated learning and explainable AI (XAI) are promising, although data privacy, algorithmic bias, and ethical ramifications are concerns. Overall, AI and ML have a great deal of promise to transform the prevention of AD, enabling precision therapy and enhancing the lives of those who are at risk.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid42116584,
year = {2026},
author = {Bala, VC and Singh, MK and Kumar, A and Tiwari, SK and Gupta, AK and Chawla, R and Kumar, S},
title = {Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.},
journal = {Protein and peptide letters},
volume = {33},
number = {1},
pages = {258-274},
doi = {10.2174/0109298665429866260217115717},
pmid = {42116584},
issn = {1875-5305},
mesh = {Humans ; *alpha-Synuclein/metabolism/genetics/antagonists & inhibitors ; *Synucleinopathies/metabolism/therapy/drug therapy/pathology ; *Parkinson Disease/metabolism/therapy/drug therapy/pathology ; Autophagy/drug effects ; Animals ; Oxidative Stress ; },
abstract = {Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.},
}

Humans
*alpha-Synuclein/metabolism/genetics/antagonists & inhibitors
*Synucleinopathies/metabolism/therapy/drug therapy/pathology
*Parkinson Disease/metabolism/therapy/drug therapy/pathology
Autophagy/drug effects
Animals
Oxidative Stress

@article {pmid42116599,
year = {2026},
author = {Saha, T and Vats, T and Mehan, S},
title = {Rituximab Beyond Oncology: Targeting B-Cell-Mediated Immunomodulatory Therapy in Neurodegenerative and Neuropsychiatric Disorders.},
journal = {Immunopharmacology and immunotoxicology},
volume = {},
number = {},
pages = {1-77},
doi = {10.1080/08923973.2026.2671714},
pmid = {42116599},
issn = {1532-2513},
abstract = {Neurological and neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and autoimmune encephalitis (AE), represent a growing global health burden due to their multifaceted pathophysiology and limited treatment options. These disorders are characterized by neuroinflammation, oxidative stress, protein aggregation, and blood-brain barrier (BBB) disruption, which contribute to neuronal damage and progressive functional decline. Emerging evidence underscores the pivotal role of B cells in driving disease progression through antibody production, antigen presentation, and cytokine release. Rituximab, a chimeric monoclonal antibody targeting CD20 on B cells, has shown promise as a potential immunomodulatory therapy for these conditions. Rituximab mediates its therapeutic effects via mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. In MS, rituximab reduces pro-inflammatory cytokines, demyelination, and immune cell activity, thereby delaying disease progression. Preclinical studies suggest its neuroprotective potential in AD and PD by mitigating B-cell-mediated neuroinflammation and oxidative stress. Furthermore, rituximab demonstrates efficacy in AE, NMOSD, and MOGAD by depleting pathogenic B cells and reducing relapse rates. Despite its proven efficacy, rituximab poses risks such as hypogammaglobulinemia, infection, and infusion-related reactions, necessitating careful patient selection, continued monitoring, and optimization of dosing regimens. This review highlights rituximab's immunomodulatory mechanisms and its expanding role in neurodegenerative and neuropsychiatric disorders. While ongoing clinical trials explore its efficacy in ALS, depression, and schizophrenia, future research should focus on identifying biomarkers of treatment response, improving CNS penetration, and combining rituximab with other therapies to enhance safety and therapeutic outcomes. Rituximab's ability to target B-cell-driven pathology positions it as a promising agent in the evolving landscape of neuroimmunology.},
}

@article {pmid42116632,
year = {2026},
author = {Han, KJ and Lv, YX and Xie, D and Zou, LH and Jiang, Q and Xie, SD and Zhang, YJ and Zhao, P and Yang, XQ and Wee, SK},
title = {Molecular Mechanistic Studies on Caffeoylquinic Acid Derivatives From Vaccinium dunalianum Wight as Dual-Target Inhibitors of AChE and BChE With In Vitro Inhibitory Evaluation and Molecular Docking.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {5},
pages = {e03013},
doi = {10.1002/cbdv.202503013},
pmid = {42116632},
issn = {1612-1880},
support = {202205AC160049//Young and Middle-Aged Academic and Technological Leaders of Yunnan Province/ ; 22267018//National Natural Science Foundation of China/ ; 32060327//National Natural Science Foundation of China/ ; 202501BD070001-027//Yunnan Fundamental Research Projects/ ; 202401AT070295//Yunnan Fundamental Research Projects/ ; 202503AC100002//Yunnan Fundamental Research Projects/ ; 202505AO120060//Yunnan Foreign Expert Program/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification ; *Molecular Docking Simulation ; *Quinic Acid/analogs & derivatives/pharmacology/chemistry/isolation & purification ; *Acetylcholinesterase/metabolism ; *Butyrylcholinesterase/metabolism ; Animals ; Rats ; Structure-Activity Relationship ; PC12 Cells ; Plant Leaves/chemistry/metabolism ; Humans ; Dose-Response Relationship, Drug ; Molecular Structure ; Plant Extracts/chemistry/pharmacology ; Cell Survival/drug effects ; },
abstract = {Alzheimer's disease (AD) involves impaired cholinergic neurotransmission, so inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is a major treatment strategy. Vaccinium dunalianum Wight leaf extracts, abundant in caffeoylquinic acids (CQAs), potently inhibit AChE (IC50 = 0.12 ± 0.01 mg/mL) and BChE (IC50 = 0.01 ± 0.01 mg/mL). Key bioactive compounds include 1-O-caffeoylquinic acid (1-CQA), chlorogenic acid (CGA), neochlorogenic acid (NCGA), and cryptochlorogenic acid (CCGA). All inhibited both enzymes concentration-dependently; 1-CQA was strongest (AChE IC50 = 0.25 ± 0.03 µM; BChE IC50 = 0.10 ± 0.01 µM), surpassing galantamine. Kinetics and docking showed reversible mixed-type inhibition targeting AChE catalytic and peripheral sites. Fluorescence quenching affirmed high-affinity binding, strongest for 1-CQA. It also showed low cytotoxicity in PC12 cells (≤10 µM). These findings reveal a dual cholinesterase inhibitory mechanism and support CQAs as promising anti-AD agents.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification
*Molecular Docking Simulation
*Quinic Acid/analogs & derivatives/pharmacology/chemistry/isolation & purification
*Acetylcholinesterase/metabolism
*Butyrylcholinesterase/metabolism
Animals
Rats
Structure-Activity Relationship
PC12 Cells
Plant Leaves/chemistry/metabolism
Humans
Dose-Response Relationship, Drug
Molecular Structure
Plant Extracts/chemistry/pharmacology
Cell Survival/drug effects

@article {pmid42118381,
year = {2026},
author = {S, K and L, G and S, PP and C, K},
title = {Aspirin as a neuroprotective scaffold in Alzheimer's disease: inflammation, oxidative stress, and future directions.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42118381},
issn = {1573-4978},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Oxidative Stress/drug effects ; *Aspirin/pharmacology/therapeutic use ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Inflammation/drug therapy/metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy ; Cyclooxygenase Inhibitors/pharmacology ; },
abstract = {Alzheimer's disease (AD) is one of the most common forms of dementia. AD is associated with memory loss and cognitive decline. Several research works have been carried out to treat AD. However, currently available treatment options are only useful in the treatment of the individual pathology of AD but not useful in disease modification. Recent research works have identified the associated effects of neuroinflammation, oxidative stress, and glial cell dysfunction in AD pathology. Aspirin is one of the most commonly used NSAIDs in the treatment of several inflammatory diseases. Aspirin inhibits cyclooxygenase (COX) enzymes through an irreversible pathway. However, aspirin also exhibits other important pharmacological properties. This review aims to highlight the potential of aspirin-based multi-target directed ligands in the regulation of AD pathology through the regulation of neuroinflammation and oxidative stress.},
}

*Alzheimer Disease/drug therapy/metabolism
Oxidative Stress/drug effects
*Aspirin/pharmacology/therapeutic use
Humans
*Neuroprotective Agents/pharmacology/therapeutic use
Inflammation/drug therapy/metabolism
Animals
Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use
Neuroinflammatory Diseases/drug therapy
Cyclooxygenase Inhibitors/pharmacology

@article {pmid42118396,
year = {2026},
author = {Kumar, R and Patel, S and Mishra, PS and Srivastava, S and Sridhar, SB and Shareef, J and Sahu, R and Tariq, M and Uddin, J and Muhsinah, AB},
title = {From Molecular Networks to Medicines: Targeting Complexity in Alzheimer's Disease (AD) Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42118396},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Molecular Targeted Therapy/methods ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multidimensional neurodegenerative disease leading to progressive loss of cognitive function and a growing health burden on the world population. Although decades of research have been conducted on this disease, current therapies have limited clinical value, mainly because researchers have not fully incorporated the intricate molecular pathways underlying its development and progression. This review summarizes current knowledge of AD pathophysiology, including amyloid beta (Aβ) dysregulation, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, oxidative stress, and synaptic breakdown. Although the amyloid- and tau-centered paradigms remain prevailing in the field, we note newer molecular targets, including secretase modulators, inflammatory signaling hubs, mitotic and autophagic regulators, epigenetics, and synaptogenesis pathways. We prioritize mechanistic, structural, cellular, and systems levels to facilitate a rational development of therapeutic understanding. The latest trends in medicinal chemistry and computational drug design, multi-target- directed ligands and hybrid scaffolds, as well as in silico ADMET optimization, are also discussed. Furthermore, we discuss the therapeutic aspects of bioinspired analogues of natural products. Lastly, we discuss the ongoing clinical development initiatives, opportunities, and major translational issues. In general, we highlight the need for integrative, mechanism-oriented, and personalized treatment approaches to propel the next generation of AD therapies.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
Animals
*Molecular Targeted Therapy/methods
Amyloid beta-Peptides/metabolism

@article {pmid42121268,
year = {2026},
author = {Cho, IH and Putra, HM and Jung, CW and Hyun, GH and Jang, HH and Hwang, IG and Kwon, SW},
title = {Neuroprotective effects of quercetin in animal models of neurodegenerative diseases: A systematic review and meta-analysis.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70699},
pmid = {42121268},
issn = {1097-0010},
support = {RS-2022-RD010385//Rural Development Administration/ ; },
abstract = {Neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease are characterized by progressive neuronal loss driven by oxidative stress and inflammation. Quercetin, a dietary flavonoid with established antioxidant and anti-inflammatory properties, has emerged as a potential neuroprotective agent. This study aimed to quantitatively synthesize and evaluate preclinical evidence regarding the impact of quercetin on neurodegenerative biomarkers and cognitive performance. A comprehensive literature search was conducted using PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL). After strict screening and selection, 19 studies were included. These evaluated the effects of quercetin on: Morris water maze (MWM) performance; inflammatory cytokines - including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10); the oxidative stress marker malondialdehyde (MDA); antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH); brain-derived neurotrophic factor (BDNF); and acetylcholinesterase (AChE) activity. Subgroup analyses based on quercetin dose (<100 mg kg[-1] versus ≥100 mg kg[-1]) and treatment duration (<28 versus ≥28 days) were performed. Quercetin improved cognitive performance significantly by reducing escape latency and improving performance on memory retention indicators. It decreased pro-inflammatory cytokines (IL-6 and TNF-α), increased IL-10, enhanced antioxidant enzyme activity (CAT, SOD, and GSH), reduced MDA levels, up-regulated BDNF, and inhibited AChE. Subgroup analyses suggested that quercetin exerted stronger effects at lower doses and with longer treatment durations, although not all subgroup differences were statistically significant. Quercetin demonstrated multi-targeted neuroprotective effects in animal models, improving cognition and modulating inflammatory, oxidative, and neurotrophic pathways. These findings support the potential of quercetin as a therapeutic agent for neurodegenerative diseases, warranting further clinical investigation. © 2026 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.},
}

@article {pmid42123478,
year = {2026},
author = {Xiao, Y and Huang, W and Chen, L and Huang, R and Guo, Y and Liu, W and Wang, X and Wang, J and Bao, J and Shu, X},
title = {Amyloid Precursor Protein Abnormalities Destabilize Membrane Ferroportin: A Novel Mechanism Underlying Early Brain Pathologies and Memory Impairment in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093892},
pmid = {42123478},
issn = {1422-0067},
support = {82371195//National Natural Science Foundation of China/ ; 82001281//National Natural Science Foundation of China/ ; No. 2024HBQZYCSB046//Intelligent Cancer Prevention and Control Platform Development and Industrialization/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Animals ; Ferroportin ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Cation Transport Proteins/metabolism/genetics ; Mice ; Humans ; *Memory Disorders/metabolism/pathology ; *Brain/pathology/metabolism ; Mice, Transgenic ; Ferroptosis ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Mutation ; Oxidative Stress ; },
abstract = {Alzheimer's disease (AD) research has primarily focused on amyloid beta (Aβ) and tau protein; however, drug development targeting these two proteins has been disappointing. Therefore, there is an urgent need to explore the novel pathogenic mechanisms underlying AD. Recently, we found that expression of the K670N/M671L-mutated amyloid precursor protein (APP) in 293T cells significantly reduced membrane ferroportin (FPN) levels. Furthermore, 2-month-old APP/PS1 mice exhibited a marked decrease in membrane FPN levels, while total FPN expression and Aβ levels remained unchanged. Further studies revealed that features of ferroptosis were present in the brains of 2-month-old APP/PS1 mice, and that treatment with ferroptosis inhibitors or iron chelation significantly alleviated early pathological changes and cognitive impairment in these animals. In addition, supplementation with an APP-FPN binding peptide during the early phase ameliorated AD-related pathologies, including Aβ deposition, neuroinflammation, oxidative stress, and synapse-associated protein deficits, in APP/PS1 mice. Collectively, our findings suggest that APP mutations may contribute to early brain pathological changes and subsequent memory impairment in AD by downregulating membrane trafficking of FPN and inducing ferroptosis, thereby providing new molecular targets for drug development.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Animals
Ferroportin
*Amyloid beta-Protein Precursor/metabolism/genetics
*Cation Transport Proteins/metabolism/genetics
Mice
Humans
*Memory Disorders/metabolism/pathology
*Brain/pathology/metabolism
Mice, Transgenic
Ferroptosis
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Mutation
Oxidative Stress

@article {pmid42125083,
year = {2026},
author = {Zhao, C and Peng, X and Cheng, Z and Yue, S and Wang, Z and Ma, L and Li, J and Shang, M},
title = {Light-based 40 Hz sensory therapy for brain disorders: physiological basis, therapeutic mechanisms, and future prospects.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1730333},
pmid = {42125083},
issn = {2296-858X},
abstract = {In recent years, 40 Hz flickering light and/or sound therapy has been confirmed to have certain therapeutic effects on Alzheimer's disease (AD), although the underlying mechanisms remain unclear. This approach has been widely explored for the treatment of various neurological disorders, but its efficacy must be verified. The induction of gamma oscillations in the brain by 40 Hz flickering light and/or sound stimulation is likely a critical component underlying its therapeutic effects across brain diseases. Elucidating the physiological basis and mechanisms by which such stimuli induce gamma oscillations may reveal its mechanisms of action in treating diseases. Although 40 Hz flickering light and/or sound intervention offers certain advantages in improving neurological function, challenges related to technical optimization and clinical promotion must be addressed. Therefore, in this paper, the underlying mechanisms through which 40 Hz flickering light and/or sound intervention induces gamma oscillations, including both neuronal and non-neuronal mechanisms, are explained. The clinical therapeutic outcomes of 40 Hz flickering light and/or sound intervention for various neurodegenerative diseases are subsequently examined, and the mechanisms underlying are summarized. Furthermore, the limitations of this therapy and corresponding improvement measures are discussed, providing a theoretical reference for further refining this technology and expanding its clinical applications. Finally, future development directions are provided, with the aims of advancing related research and facilitating the application of this therapy in the treatment of brain diseases.},
}

@article {pmid42111521,
year = {2026},
author = {Guo, B and Wang, J and Lou, F and Yuan, B and Chen, Z and Tang, C and Chen, W and Yi, F and Jiang, J and Hu, G and Cong, C and Lu, Y},
title = {Graphene field-effect transistor based multiplexed sensing platform for simultaneous detection of multiple Alzheimer's disease biomarkers.},
journal = {RSC advances},
volume = {16},
number = {26},
pages = {23937-23944},
pmid = {42111521},
issn = {2046-2069},
abstract = {Simultaneous detection of multiple biomarkers for one disease using a single drop of body fluid is challenging yet critical to confirm symptoms in the early stage. This study presents the development of a graphene field-effect transistor (GFET)-based multiplexed sensing platform designed for overcoming this obstacle. The platform utilizes a hexamethyldisilazane (HMDS) blocking layer as a hydrophobic treatment to enable recognition element (probe/aptamer) modifications within a small chip area (3 × 3 mm[2]), and this further enables simultaneous detection of multiple targets (multi-targets) in complex biological samples. The optimized aptamer/probe functionalization also enhances the specificity, sensitivity, and accuracy of the sensor. The technology was demonstrated with Alzheimer's disease (AD) biomarkers as a case study. Two distinctive biomarkers, hsa-miR-125b and Aβ42, are detected simultaneously with distinguishable signatures, and the lowest tested concentration is 1 fM. The cross-check experiments also show the effectiveness of the multi-target detection capability. This concise platform paves the way for accurate detection of early-stage diseases when the simultaneous identification of multiple biomarkers is required.},
}

@article {pmid42111940,
year = {2026},
author = {Ismail Al-Khaleel, R and Kalenahalli, Y and Hemalatha, S and Baker, S and Raj, SN and Rangappa, KS and Gowda, S and Siddaiah, C},
title = {Metabolomic analysis of Pennisetum glaucum seed extracts using advanced LC-MS/MS and Q-TOF technology.},
journal = {Journal of food science and technology},
volume = {63},
number = {5},
pages = {962-970},
pmid = {42111940},
issn = {0022-1155},
abstract = {UNLABELLED: Pearl millet (Pennisetum glaucum) is a cereal widely cultivated and grown in Africa and the Indian subcontinent for centuries. The present investigation aims to use LC-MS/MS to analyze the secondary metabolites present in pearl millet seeds using different solvents such as methanol, hexane, chloroform, and ethyl acetate. METLIN software was used to identify the metabolites. The analysis revealed the presence of 650 metabolites, among which 145 were commonly found in all the solvent extracts. The major classes of identified metabolites are terpenoids, flavonoids, sterols, amino acids, fatty acids, glycoconjugates, and carbohydrates. 80% methanolic extract and ethyl acetate extract yielded the highest concentrations of terpenoid (23%) and flavonoid (17%). The enrichment analysis was performed to statistically examine and identify the metabolites present in the metabolomic library dataset. In the hexane extract, notable metabolites such as quercetin and rutin were identified, which possess potential for the management of Alzheimer's disease due to their neuroprotective effects (p < 4e-35). In the methanol extract, metabolites like gallic acid and caffeic acid were associated with uremia treatment due to their antioxidant activity (p < 5e-37). Overall, the present study provides an overview of the metabolites present in the pearl millet seeds and the nutritive as well as therapeutic potential of these millets in the management of human diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-025-06328-6.},
}

@article {pmid42112453,
year = {2025},
author = {Usman, M and Ashebir, S and Okey-Mbata, C and Yun, Y and Kim, S},
title = {Neuroengineering Frontiers: A Selective Review of Neural Interfaces, Brain-Machine Interactions, and Artificial Intelligence in Neurodegenerative Diseases.},
journal = {Applied sciences (Basel, Switzerland)},
volume = {15},
number = {21},
pages = {},
pmid = {42112453},
issn = {2076-3417},
support = {SC1 NS122448/NS/NINDS NIH HHS/United States ; UG3 EB036466/EB/NIBIB NIH HHS/United States ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), present a growing public health challenge globally. Recent advancements in neurotechnology and neuroengineering have significantly enhanced brain-computer interfaces, artificial intelligence, and organoid technologies, making them pivotal instruments for diagnosis, monitoring, disease modeling, treatment development, and rehabilitation of various diseases. Nonetheless, the majority of neural interface platforms focus on unidirectional control paradigms, neglecting the need for co-adaptive systems where both the human user and the interface continually learn and adapt. This selected review consolidates information from neuroscience, artificial intelligence, and organoid engineering to identify the conceptual underpinnings of co-adaptive and symbiotic human-machine interaction. We emphasize significant shortcomings in the advancement of long-term AI-facilitated co-adaptation, which permits individualized diagnostics and progression tracking in Alzheimer's disease and Parkinson's disease. We concentrate on incorporating deep learning for adaptive decoding, reinforcement learning for bidirectional feedback, and hybrid organoid-brain-computer interface platforms to mimic disease dynamics and expedite therapy discoveries. This study outlines the trends and limitations of the topics at hand, proposing a research framework for next-generation AI-enhanced neural interfaces targeting neurodegenerative diseases and neurological disorders that are both technologically sophisticated and clinically viable, while adhering to ethical standards.},
}

@article {pmid42113681,
year = {2026},
author = {Wang, S and Yuan, X and Wang, T and Yang, M and Dong, P and Han, H},
title = {Mechanisms and Therapeutic Targeting of the GutMicrobiota-Immune-Brain Axis in Alzheimer's Disease.},
journal = {Immunological investigations},
volume = {},
number = {},
pages = {1-31},
doi = {10.1080/08820139.2026.2669375},
pmid = {42113681},
issn = {1532-4311},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disease globally. The main pathological features of AD are amyloid-β (Aβ) deposition and tau hyperphosphorylation. Recent studies suggest that the gut microbiota-immunity-brain axis plays an important role in the onset and progression of AD. Gut microbiota dysbiosis may impair intestinal barrier integrity and promote the entry of pro-inflammatory mediators into the circulation. Pro-inflammatory signals in the bloodstream may further activate the central immune system, drive microglial polarization, and increase the release of inflammatory factors in the brain. The resulting neuroinflammatory cascade may aggravate Aβ accumulation, tau phosphorylation, and cognitive impairment, although this mechanism has not been conclusively established in humans.

METHODS AND RESULTS: Based on relevant literature on AD, gut microbiota, immunity, neuroinflammation, and the gut-brain axis, this article systematically reviews the mechanism of action of the microbiota-immunity-brain axis in AD. Current intervention strategies targeting this axis, including probiotics, fecal microbiota transplantation, dietary interventions, and traditional Chinese medicine, were also discussed. Such intervention measures have the potential to regulate the balance of the gut microbiota, reduce neuroinflammation, and slow the progression of AD pathology.

CONCLUSION: It is essential to integrate multi-omics approaches in future research to deepen the understanding of AD pathogenesis and support the development of more precise and personalized treatment strategies.},
}

@article {pmid42115432,
year = {2026},
author = {Ferré, CG and Pallàs, M and Franco, R},
title = {Molecular and statistical weaknesses of the p-tau217/Aβ1-42 plasma ratio for alzheimer's diagnosis.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {},
pmid = {42115432},
issn = {1432-1440},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; *Biomarkers/blood ; *Peptide Fragments/blood ; Reproducibility of Results ; },
abstract = {The FDA's approval of the Lumipulse G p-tau217/Aβ1-42 plasma ratio enhances access to Alzheimer's diagnostics but risks confusing convenience with biological accuracy. The assay is scalable and non-invasive, yet it relies on a ratio of two markers that are unstable and only partly specific to the disease, raising concerns about reproducibility and interpretation. The reported performance is solid in carefully selected groups, but is likely to be less robust in broader real-world populations with lower disease prevalence, mixed pathologies, and higher comorbidity. If biomarker-based enrollment is shaped by imperfect specificity, misclassification may propagate into trial recruitment, treatment-effect estimates, and downstream validation. This concern is amplified when biomarkers are validated within partially circular frameworks in which plasma assays, positron emission tomography, cerebrospinal fluid markers, and clinical diagnosis reinforce one another without fully independent neuropathological confirmation. Blood-based assays remain promising, but their clinical use should be guided by rigorous analytical scrutiny, broad validation across diverse populations, standardized pre-analytical handling, and transparent data sharing. The aim of biomarker science should be not striking receiver operating characteristic curves in curated cohorts, but biological fidelity across human heterogeneity and validation grounded in mechanism. Until then, the p-tau217/Aβ1-42 ratio is best regarded as a useful contextual or research tool rather than a standalone diagnostic benchmark, so that precision medicine does not rest on associations whose causal and mechanistic basis remains insufficiently established. Its most appropriate use may be in longitudinal monitoring within the same individual, where changes over time may be more informative than a single threshold-based diagnostic result.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Amyloid beta-Peptides/blood
*tau Proteins/blood
*Biomarkers/blood
*Peptide Fragments/blood
Reproducibility of Results

@article {pmid42115835,
year = {2026},
author = {Fu, Q and Yin, X and Xu, S},
title = {Disentangling treatment status from disease severity in studies of diabetes and Alzheimer's disease biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71465},
doi = {10.1002/alz.71465},
pmid = {42115835},
issn = {1552-5279},
support = {824774630//National Natural Science Foundation of China/ ; 82274643//National Natural Science Foundation of China/ ; 20234Y0023//Shanghai Municipal Health Commission/ ; },
}

@article {pmid42116113,
year = {2026},
author = {Li, Y and Hu, C and Xia, C and Wang, X and Zhou, X and Xu, R and Li, Y and Mo, F and Zhao, B and Xu, L and Zhu, C and Chen, Z},
title = {A novel nasal mucosal peptide-modified co-delivery system for ginsenoside Rg1, Rb1, and notoginseng saponin R1 in the amelioration of AD.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04532-w},
pmid = {42116113},
issn = {1477-3155},
support = {202510315035//National Innovation and Entrepreneurship Training Program for Undergraduate/ ; 82304729//National Natural Science Foundation of China/ ; 82574587//National Natural Science Foundation of China/ ; BK20230457//Natural Science Foundation of Jiangsu Province/ ; ZYXYL2024-005//Scientific Research Foundation of Nanjing University of Chinese Medicine/ ; },
abstract = {The drug delivery for Alzheimer's disease (AD) faces substantial obstacles owing to the presence of the blood-brain barrier (BBB). This circumstance highlights the nose-brain route as pivotal for enhancing drug distribution to the brain. As the efficiency of brain entry is constrained by the physiological barrier of the nasal cavity, the development of strategies to efficiently traverse this barrier is imperative for enhancing the effectiveness of AD treatment. In the present study, a cell-penetrating peptide (CPPs) named LK4, which originates from mastoparan-L (MPL), was employed. Its capacity to efficiently penetrate the physiological barrier of the nasal cavity was demonstrated. LK4 was modified into polydopamine (PDA) nanoparticles to construct nanoparticles containing ginsenoside Rg1, ginsenoside Rb1, and notoginseng saponin R1 (TGS), designated as LK4-TGS-PDA. Experiment results reveal that the LK4-TGS-PDA drug delivery system can enhance the uptake of olfactory neurons and promote epithelial transport. In an in vitro nasal mucosal barrier model, LK4 modification increased the apparent permeability coefficients of R1, Rg1, and Rb1 by 1.2-, 1.2-, and 12-fold, respectively, compared to unmodified nanoparticles. Following nasal administration, the brain concentrations of R1, Rg1, and Rb1 increased by 19-fold, 30-fold, and 15-fold, respectively, and the relative brain bioavailability reached 933.1%, 1375.0%, and 1144.4%, respectively. In the model of AD induced by amyloid-beta 1-42 (Aβ1-42), it was confirmed that LK4-TGS-PDA NPs can significantly improve cognitive dysfunction, with escape latency reduced by 30.3%, platform crossings increased by 5.4-fold, and target quadrant time extended by 2.4-fold, as well as reduce the effects of inflammation in the brain, with IL-1β, IL-6, and TNF-α decreased by 44.05%, 53.49%, and 84.40%, respectively. The present investigation outcomes reveal that the engineered LK4-TGS-PDA NPs demonstrates effectiveness and efficiency as a drug delivery approach for the nose-brain pathway, offering valuable insights and prospects for enhancing AD treatment.},
}

@article {pmid42106468,
year = {2026},
author = {Santos, ACC and Corrêa, JL and Duarte, RMF and Malta, SM and Rodrigues, TS and de Oliveira Santos, D and de Faria, PR and do Prado Mascarenhas, FNA and Zanon, RG and Cassemiro, NS and Carollo, CA and Espindola, FS and Martins, MM and Mendes-Silva, AP and Bonetti, AM and Dos Santos, AR and Ueira-Vieira, C},
title = {Bacterial polar metabolites modulate β-amyloid toxicity and cholinergic dysfunction in models of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52291-3},
pmid = {42106468},
issn = {2045-2322},
support = {APQ-00269-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 403193/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; APQ-03613-17; APQ-02766-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais , Brasil/ ; },
abstract = {Alzheimer's disease is characterized by progressive neurodegeneration driven by β-amyloid (Aβ) toxicity, oxidative stress, and cholinergic dysfunction. In this study, we investigated whether polar metabolites derived from a cultivable bacterial isolate could modulate Aβ-associated neurodegenerative phenotypes in complementary experimental models. A bioactivity-guided approach identified an aqueous fraction with high antioxidant capacity in DPPH, FRAP, and ORAC assays. In a transgenic Drosophila melanogaster model expressing human Aβ, treatment with this fraction significantly reduced amyloid accumulation and attenuated neurodegenerative histopathological alterations. In human SH-SY5Y neuronal cultures, the metabolites improved cell viability under therapeutic, but not preventive, conditions following exposure to aggregated Aβ. The aqueous fraction also exhibited significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Whole-genome sequencing assigned the bioactive isolate to the genus Providencia, with comparative genomic analyses suggesting its placement within a distinct taxonomic lineage. Metabolomic profiling by LC-ESI-MS/MS revealed a diverse set of polar metabolites, including metabolites putatively annotated based on spectral matching, previously associated with neuroprotective and cholinesterase-modulating activities. Collectively, these findings demonstrate that bacterial polar metabolites can modulate key pathological features of Alzheimer's disease, supporting their relevance for mechanistic studies of Aβ toxicity and cholinergic dysfunction.},
}

@article {pmid42107415,
year = {2026},
author = {Stepanchuk, AA and Joseph, JT and Lashley, T and Stys, PK},
title = {Disentangling amyloid polymorphs in normal aging and Alzheimer's disease using dual-probe spectral imaging.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {51-59},
doi = {10.1016/j.neurobiolaging.2026.04.009},
pmid = {42107415},
issn = {1558-1497},
abstract = {Variability in Alzheimer's disease (AD) clinical presentation complicates mechanistic studies and therapeutic outcome prediction. Brain protein aggregate load does not directly correlate with clinical symptoms; however, different subtypes of AD have been reported to exhibit structural variation (polymorphism) of aggregates. Little is known about the structural diversity of the deposits in cognitively normal aged brains. This study investigates the structural heterogeneity of amyloid aggregates in the hippocampus and their association with age- and disease-related pathology. Post-mortem hippocampal tissue from cognitively normal aged controls and AD patients was co-stained with the amyloid-sensitive dyes BSB and MCAAD-3 and imaged across various subregions using spectral fluorescence microscopy. Machine learning analysis of spectral data differentiated amyloid polymorphs between cognitively normal and Alzheimer's cases. Our analysis revealed distinct spectral features across the amyloid plaques, neurofibrillary tangles and the background tissue parenchyma associated with AD compared to those observed in cognitively normal aging, irrespective of overall aggregate load. This study underscores the importance of amyloid polymorphism in determining the clinical impact of protein pathology in AD. Our findings highlight that focusing on amyloid structure rather than total load can aid in advancing personalized approaches in the diagnosis and treatment of neurodegenerative diseases.},
}

@article {pmid42107621,
year = {2026},
author = {Khattab, NA and El Kadeem, A and Goda, AE and El-Mahdy, NA and El-Shitany, N},
title = {Aluminum chloride in Alzheimer's disease: A dual focus on molecular mechanisms and rat experimental models.},
journal = {Experimental neurology},
volume = {403},
number = {},
pages = {115814},
doi = {10.1016/j.expneurol.2026.115814},
pmid = {42107621},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a leading cause of dementia among middle-aged and elderly individuals globally. Animal models of AD are widely used to investigate disease mechanisms and evaluate potential treatments for disease modification. Among non-genetically modified models, aluminum (Al[3+]) induced neurotoxicity has been widely employed to mimic key features of AD, including neuroinflammation and cognitive decline. This review comprehensively elucidates current evidence on the molecular and cellular mechanisms underlying Al[3+]-induced AD-like pathology, including amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic system impairment, synaptic plasticity deficits, apoptosis, metal ion dyshomeostasis, and epigenetic alterations. This review critically discusses methodological variables that significantly influence experimental outcomes in Al[3+]-based models, including dosage, route of administration, exposure duration, and animal age and gender. Moreover, this review emphasizes the translational significance, advantages, and limitations of the Al[3+]-induced model by merging mechanistic insights with experimental design considerations, offering guidelines for its optimal application in AD research and treatment development.},
}

@article {pmid42107748,
year = {2026},
author = {Suriyaamporn, P and Wongprayoon, P and Pannakkong, W and Pamornpathomkul, B and Ngawhirunpat, T and Rojanarata, T and Opanasopit, P},
title = {Development of AI-assisted 3D-printed degradable hydrogel microneedles for transdermal delivery of progesterone-loaded solid lipid nanoparticles: a novel approach to slowing Alzheimer's disease progression.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126967},
doi = {10.1016/j.ijpharm.2026.126967},
pmid = {42107748},
issn = {1873-3476},
abstract = {Progesterone (PG) is used to slow the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) in postmenopausal women. However, PG exhibits high lipophilicity, resulting in strong binding to skin tissues and plasma proteins, which may limit its systemic transport via transdermal routes. Solid lipid nanoparticles (SLNs) have been highlighted for their potential to enhance drug solubility and facilitate brain-targeted drug delivery for AD treatment. Microneedles (MNs) offer an advanced microtechnology for transdermal drug delivery, significantly improving drug permeation into the skin. However, traditional MNs fabrication methods face challenges related to shape control, dosage precision, high costs, and time consumption. Recent advancements in 3D printing technology offer a promising solution to these limitations. This study aimed to design and evaluate 3D-printed MNs-loaded with PG-SLNs for AD treatment. Biodegradable resin was utilized to fabricate MNs, aided by a Convolutional Neural Networks (CNNs) prediction model for improved accuracy. Mechanical strength, penetration efficiency, degradation, in vitro and in vivo drug delivery efficiency, cellular toxicity, and stability were evaluated. The optimized MNs, with a height of 756.98 ± 14.78 µm, effectively penetrated the skin barrier. SLNs exhibited a particle size of 308.91 ± 1.66 nm, PDI of 0.19 ± 0.08, and ZP of -30.03 ± 1.19 mV. The MNs retained sufficient mechanical strength post-drug loading, enabled efficient transdermal PG delivery, exhibited no cytotoxicity to neuronal cells, and remained physicochemically stable for up to 3 months. This study highlights the potential of 3D-printed MN patches as a novel transdermal drug delivery system, demonstrating practical feasibility for medical applications.},
}

@article {pmid42107892,
year = {2026},
author = {Chen, G and Zhao, C and Wang, C and Chen, G and Shi, J and Chen, H},
title = {Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.},
journal = {International immunopharmacology},
volume = {182},
number = {},
pages = {116781},
doi = {10.1016/j.intimp.2026.116781},
pmid = {42107892},
issn = {1878-1705},
abstract = {Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.},
}

@article {pmid42108759,
year = {2026},
author = {Meng, Q and Li, J and Xu, G and Zhang, W and Cao, R and Cai, K},
title = {Ginsenoside Rh2 Alleviates Alzheimer Disease Models via Effects on Ferroptosis-Related Neuroinflammation.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70860},
doi = {10.1002/jbt.70860},
pmid = {42108759},
issn = {1099-0461},
support = {YKK23216//Nanjing Health Science and Technology Development Special Fund/ ; ST222102//Major Sports Research Projects of Jiangsu Provincial Sports Bureau/ ; LKZ2025004//Jiangsu Elderly Health Scientific Research Project/ ; },
mesh = {Animals ; *Ginsenosides/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Ferroptosis/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; Male ; Oxidative Stress/drug effects ; Peptide Fragments ; },
abstract = {Ginsenosides are the primary active constituents derived from the dried roots of ginseng, a staple in traditional Chinese medicine. This study aimed to evaluate the therapeutic efficacy of the Ginsenoside Rh2 (Rh2) monomer in both in vitro and in vivo models of Alzheimer disease (AD). An in vivo AD cell model was established by stimulating N2a mouse neuroblastoma cells with β-amyloid (Aβ) 1-42, while APP/PS1 transgenic mice served as the in vivo model. In vitro, Aβ1-42-stimulated N2a cells were co-incubated with 40 or 80 μM Rh2 for 24 h. In vivo, APP/PS1 mice received daily intraperitoneal injections of Rh2 (20 mg/kg) for 5 weeks. Our results demonstrated that Rh2 treatment significantly enhanced the viability of N2a cells and ameliorated mitochondrial membrane potential dysregulation. Furthermore, Rh2 attenuated oxidative stress by reducing reactive oxygen species production and decreasing malondialdehyde levels. It also suppressed the hypersecretion of pro-inflammatory mediators, including nitric oxide, interleukin-1β (IL-1β), and IL-6, in Aβ-treated cells. Mechanistically, Rh2 exerted potent anti-ferroptotic and anti-inflammatory effects via the activation of the Nrf2/GPX4 signaling pathway, which ultimately translated to improved spatial learning and memory in APP/PS1 mice. These findings elucidate a novel mechanistic paradigm for Rh2, highlighting its potential as a therapeutic candidate for AD drug development.},
}

Animals
*Ginsenosides/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
Mice, Transgenic
Disease Models, Animal
*Ferroptosis/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
Amyloid beta-Peptides/metabolism
Cell Line, Tumor
Male
Oxidative Stress/drug effects
Peptide Fragments

@article {pmid42109911,
year = {2026},
author = {Choi, S and Park, S and Jung, YH and Oh, MS and Yu, KH and Lee, BC and Lee, M},
title = {Comparative risk of dementia between direct oral anticoagulants and warfarin after atrial fibrillation related ischemic stroke.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1718536},
pmid = {42109911},
issn = {1663-4365},
abstract = {INTRODUCTION: Direct oral anticoagulants (DOAC) have been associated with a reduced risk of dementia compared to warfarin in patients with atrial fibrillation (AF) without prior stroke. However, the impact of DOAC on dementia risk in AF-related ischemic stroke survivors is unclear.

METHODS: We conducted a retrospective, nationwide cohort study using the Korean National Health Insurance Service database. We identified patients with newly diagnosed ischemic stroke and concurrent AF who began DOAC or warfarin therapy within one month after stroke. Incidence of all-cause dementia, Alzheimer's dementia (AD), and vascular dementia (VaD) was compared between groups using multivariable Cox models with inverse probability of treatment weighting.

RESULTS: A total of 3,112 patients (mean age 70.6 ± 9.5 years; 66.6% male) were analyzed, including 2,919 DOAC users and 193 warfarin users. Over a mean follow-up of 3.63 years, 673 all-cause dementia cases (538 AD, 168 VaD) occurred. After IPTW, DOAC use was associated with higher risks of all-cause dementia (HR 1.16, 95% CI 1.04-1.30) and AD (HR 1.85, 95% CI 1.62-2.13) but a lower risk of VaD (HR 0.54, 95% CI 0.45-0.66) compared to warfarin.

DISCUSSION: In this retrospective nationwide cohort of AF-related ischemic stroke survivors, DOAC use was associated with a higher incidence of all-cause dementia and Alzheimer's dementia, but a lower incidence of vascular dementia, compared with warfarin. These observational findings suggest that anticoagulant type may be differentially associated with subsequent dementia subtypes in this high-risk population and should be interpreted with caution.},
}

@article {pmid42109914,
year = {2026},
author = {Fu, X and Huang, J and Liu, Y and Li, H and Zhang, Y},
title = {Unraveling the anti-neuroinflammatory mechanisms of Cervus cucumis polypeptide injection in Alzheimer's disease: insights from network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1797302},
pmid = {42109914},
issn = {1663-4365},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing global prevalence, in which neuroinflammation serves as a critical pathological driver exacerbating cognitive decline. While current therapies offer limited symptomatic relief, multi-target strategies are urgently needed. Cervus cucumis polypeptide injection (CCPI), a traditional Chinese medicine (TCM) formulation, has demonstrated anti-inflammatory properties; however, its mechanisms of action against AD remain unclear. This study aimed to elucidate the anti-AD potential mechanisms of CCPI using an integrated approach combining network pharmacology, molecular docking, molecular dynamics (MD) simulation, and experimental validation.

METHODS: Active components and corresponding targets of CCPI were retrieved from the TCMSP database, while AD-related targets were collected from Genecards, OMIM, and DrugBank. Potential therapeutic targets were identified by intersecting drug and disease targets, followed by protein-protein interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and MD simulations were performed to evaluate interactions between potential active components and key targets. In vitro experiments were conducted on Aβ25-35-induced BV2 microglial cells to assess cell viability (CCK-8 assay), inflammatory cytokine levels (ELISA), and protein expression (Western blot) related to the neuroinflammation pathway and microglial polarization.

RESULTS: A total of 28 active components and 50 common targets of CCPI for AD treatment were identified. Linoleic acid (LA) was determined to be a potential active component, with IL-6 as the key target based on PPI network topology. Molecular docking and MD simulation confirmed a stable binding affinity between LA and IL-6. KEGG analysis revealed significant enrichment in the HIF-1 signaling pathway, particularly the IL-6/STAT3/VEGF signaling pathway. In vitro, CCPI treatment significantly enhanced cell viability and attenuated the pro-inflammatory response, as evidenced by reduced levels of IL-6, IL-1β, and TNF-α, decreased the expression of the pro-inflammatory marker iNOS. Concurrently, it elevated the expression of the anti-inflammatory/repair-associated marker CD206. Western blot analysis further verified that CCPI suppressed IL-6/STAT3 activation while upregulating VEGF expression. Additionally, LA alone significantly reduced IL-6 levels and STAT3 phosphorylation, decreased the expression of iNOS, and increased the expression of CD206, with therapeutic efficacy comparable to CCPI.

CONCLUSION: CCPI exerts neuroprotective effects in AD models by regulating the IL-6/STAT3/VEGF pathway, downregulating the expression of the inflammation-related iNOS protein, upregulating the expression of the CD206 protein associated with anti-inflammatory and reparative functions, remodeling the functional state of microglia, inhibiting their pro-inflammatory responses, and enhancing their reparative functions. Its potential active component, LA, likely mediates this effect by stably binding to and inhibiting IL-6, thus suppressing the downstream STAT3 phosphorylation that drives inflammatory activation.},
}

@article {pmid42100782,
year = {2026},
author = {Zhang, R and Sun, H and Di, Y and Cao, H and Zhang, C and Yao, H and Yan, H and Ding, D and He, Q and Wu, T},
title = {Sleep quality metrics combined with virtual reality motion parameters enhance early detection of mild cognitive impairment.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1727576},
pmid = {42100782},
issn = {1664-0640},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive and motor deficits. With its global prevalence increasing rapidly and no effective treatment available, early identification of high-risk individuals is critical. This study investigated the relationship between motor parameters extracted from virtual reality (VR) tasks, combined with sleep-related measures, and cognitive impairment in patients with mild cognitive impairment (MCI). Our goal was to determine whether integrating VR-derived digital markers with sleep quality metrics could provide an objective and clinically applicable tool for early detection.

METHODS: 66 participants were recruited, including 28 healthy controls (HC) and 38 patients with MCI. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). All participants performed two scenario-based VR tasks, during which task completion time, accuracy, and overall performance scores were recorded. Group differences were evaluated using independent-samples t-tests, and these behavioral features and sleep quality metrics were further incorporated into ROC analyze to assess predictive performance for distinguishing MCI from HC.

RESULTS: Compared with HC, patients with MCI reported significantly poorer sleep quality based on the Pittsburgh Sleep Quality Index (PSQI) and subdomains such as sleep latency and habitual sleep efficiency. In the VR tasks, MCI patients required more time and achieved lower accuracy than HC, consistent with MoCA and MMSE scores. Correlation analysis confirmed strong associations between VR performance metrics and cognitive test scores. Importantly, integrating VR-derived digital markers with sleep parameters yielded superior predictive accuracy for MCI (AUC = 0.863; sensitivity = 86.84%; specificity = 71.43%; p < 0.001) compared with single-modality models.

CONCLUSION: VR-based cognitive and sensorimotor tasks, when combined with sleep quality assessments, offer a robust and noninvasive approach for the early identification of prodromal AD. This multimodal strategy holds promise for enhancing clinical decision-making and enabling timely interventions.},
}

@article {pmid42100836,
year = {2026},
author = {Kaczmarek-Kryszak, KA and Dobrzyńska, M and Banaszak, M and Drzymała-Czyż, S},
title = {A comprehensive systematic review of human trials investigating herbal treatments for Alzheimer's disease and dementia.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-55},
doi = {10.1017/neu.2026.10085},
pmid = {42100836},
issn = {1601-5215},
abstract = {OBJECTIVE: Dementia is a group of symptoms, characterized by a loss of cognition that interferes with everyday tasks, difficulty focusing, planning, problem solving, and behavioral changes, such as apathy, anxiety, or depression. The leading cause of dementia is Alzheimer's disease, but vascular dementia or mild cognitive impairment are also frequently occurring. There are six drugs legislated in Europe for use in the treatment of dementia. There are unmet clinical needs to find more effective, better tolerated or complementary therapeutic options. The aim of this study is to comprehensively analyze the results of clinical trials and other human studies regarding the efficacy and safety of herbal interventions used in patients with dementia.

METHODS: We enrolled a total of 48 studies for this systematic review, of which 27 were included into the statistical analysis of effect size (Cohen's d).

RESULTS: We found significant improvements mainly after administration of Ginkgo biloba, Crocus sativus, Salvia officinalis, and Melissa officinalis.It should be emphasized that some herbs and herbal formulations demonstrated efficacy comparable to that of donepezil, a widely used and approved medication, suggesting potential for phytopharmaceutical therapies as complementary approaches. In some studies, the observed effects were similar to those reported for conventional treatments, indicating promising directions for further research in Alzheimer's disease and dementia.

CONCLUSION: In light of the evidence, phytopharmaceuticals have a promising role as a co-therapeutic option or alternative for patients with dementia who do not tolerate or have contraindications to standard medications. However, further research is necessary to translate these initial promising results into clinical practice.

SUMMATIONS: Phytopharmaceuticals have a promising role as a complementary or alternative option for dementia patients who cannot tolerate or respond to standard medications. Certain phytopharmaceuticals demonstrated comparable short-term symptomatic effects to standard treatments in small trials; however, evidence is insufficient to support equivalence or superiority.

CONSIDERATIONS: Many of the studies reviewed are limited by very small sample sizes, which is associated with a high risk of bias when interpreting large effect sizes (Cohen's d). The short duration of interventions (often only 3 to 6 months) is insufficient to assess whether phytotherapeutics can constitute disease-modifying treatments (DMTs).},
}

@article {pmid42101516,
year = {2026},
author = {Zhou, B and Wu, X and Wang, J and Li, L and Xu, H and Shao, W},
title = {Compatibility of Acorus tatarinowii Schott and Polygala tenuifolia Willd. alleviate Alzheimer's disease through regulating Nos2-mediated calcium signaling pathway.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42101516},
issn = {1573-6903},
support = {ZY2023M027//the General Project of the Administration of Traditional Chinese Medicine of Hubei Province/ ; },
mesh = {PC12 Cells ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Amyloid beta-Peptides/metabolism ; *Polygala/chemistry ; *Calcium Signaling/drug effects/physiology ; *Nitric Oxide Synthase Type II/metabolism ; *Acorus/chemistry ; *Plant Extracts/pharmacology/therapeutic use ; Cell Survival/drug effects ; Peptide Fragments/metabolism ; },
abstract = {Herb pair of Acorus tatarinowii Schott (ATS) and Polygala tenuifolia Willd. (PTW) is a classic drug pair in the treatment of Alzheimer's disease (AD), However, the mechanism by which the drug pair acts on AD is currently unknown. To address this, we constructed a PC12 cellular AD model using amyloid-beta peptide (Aβ) (25-35), follow by treating with different concentrations of ATS and PTW alone or their combination (1:1). The cell viability and Aβ-40, Aβ-42 and AQP4 expression were detected. In addition, RNA-sequencing combined with network pharmacology was performed to investigate the action mechanism of ATS and PTW, and the results were validated using in vitro experiments. The results showed that at drug-acting concentrations less than 100 mg/L, both single-agent and combined treatments of ATS and PTW increased the protective effects on PC12 cell, and the herb pair was superior to single-agent. In addition, both single-agent and combined treatments of ATS and PTW (at concentration of 100 mg/L) decreased Aβ-40, Aβ-42 and AQP4 expression compared with AD model. Further RNA-sequencing combined with network pharmacology analysis suggested that the underline action mechanism might be associated with Nos2-mediated calcium signaling pathway regulated. In vitro validation experiments showed that Nos2 overexpression increase the levels of Aβ-40, Aβ-42, AQP4, p-Tau, CaM, and p-CaMKII, which were reversed by the combination treatment of ATS and PTW. In conclusion, this work indicates that ATS and PTW combination might alleviate an Aβ-induced cellular model through regulating Nos2 - mediated calcium signaling pathway.},
}

PC12 Cells
Animals
*Alzheimer Disease/drug therapy/metabolism
Rats
Amyloid beta-Peptides/metabolism
*Polygala/chemistry
*Calcium Signaling/drug effects/physiology
*Nitric Oxide Synthase Type II/metabolism
*Acorus/chemistry
*Plant Extracts/pharmacology/therapeutic use
Cell Survival/drug effects
Peptide Fragments/metabolism

@article {pmid42103387,
year = {2026},
author = {Laugesen, K and Skjærbæk, C and Okkels, N and Møller, HJ and Borghammer, P and Gottrup, H and Parkner, T},
title = {ODIN Biobank: a Danish cohort for dementia research- cohort profile.},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e114084},
doi = {10.1136/bmjopen-2025-114084},
pmid = {42103387},
issn = {2044-6055},
mesh = {Humans ; Female ; Denmark ; Male ; Aged ; *Biological Specimen Banks ; *Dementia/cerebrospinal fluid/blood/diagnosis ; Biomarkers/cerebrospinal fluid/blood ; Aged, 80 and over ; Cohort Studies ; Middle Aged ; Alzheimer Disease/cerebrospinal fluid/blood ; Cognitive Dysfunction/cerebrospinal fluid/blood ; },
abstract = {PURPOSE: Biomarkers related to the diagnosis, prognosis and treatment of dementia will play a key role in future clinical practice. The overarching aim of the ODIN (blood and cerebrospinal fluid) Biobank is to study biomarkers for dementia and contribute to the transition from cerebrospinal fluid to blood-based biomarkers.

PARTICIPANTS: ODIN recruited 451 patients (median age 74 years, 53% females) referred to the Department of Neurology at Aarhus University Hospital, Denmark, for diagnostic assessment of dementia. Enrolment started in March 2020 and ended in July 2025. Patients referred for a lumbar puncture were eligible for inclusion. Cerebrospinal fluid and blood samples (plasma, serum and buffy coat) were stored at -80°C. Information about sociodemographic, educational level, dementia subtype, cognitive test scores, neuroimaging results, hypertension, diabetes, height, weight, alcohol consumption and smoking was collected.

FINDINGS TO DATE: The most frequent diagnoses were Alzheimer's disease (n=268, 59%), frontotemporal dementia (n=26, 5.8%) and mixed Alzheimer's and vascular disease (n=23, 5.1%). N=82 (18%) were cognitively unimpaired or had mild cognitive impairment but not dementia. The median Mini-Mental State Examination score was 23 (IQR: 20-26) and the median Addenbrooke's Cognitive Examination score was 68 (IQR: 58-77).

FUTURE PLANS: ODIN will contribute to the development, validation and implementation of new biomarkers related to diagnosis, prognosis and treatment of dementia. Furthermore, the cohort will assist the transition from cerebrospinal fluid to blood-based biomarkers.},
}

Humans
Female
Denmark
Male
Aged
*Biological Specimen Banks
*Dementia/cerebrospinal fluid/blood/diagnosis
Biomarkers/cerebrospinal fluid/blood
Aged, 80 and over
Cohort Studies
Middle Aged
Alzheimer Disease/cerebrospinal fluid/blood
Cognitive Dysfunction/cerebrospinal fluid/blood

@article {pmid42104655,
year = {2026},
author = {Sharmin, T and Doecke, JD and Chatterjee, P and Pedrini, S and Sohrabi, HR and Ashton, NJ and Zetterberg, H and Garg, ML and Blennow, K and Martins, RN},
title = {Circulating Sphingomyelins Correlate With Plasma T-Tau in Cognitively Unimpaired Older Adults at Risk of Developing Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {5},
pages = {e70436},
pmid = {42104655},
issn = {1471-4159},
support = {2018-02532//MQ Research Seeding Grant, Macquarie University/ ; 681712//MQ Research Seeding Grant, Macquarie University/ ; 201809-2016862//MQ Research Seeding Grant, Macquarie University/ ; 2017-00915//MQ Research Seeding Grant, Macquarie University/ ; FO2017-0243//MQ Research Seeding Grant, Macquarie University/ ; JPND2019-466-236//MQ Research Seeding Grant, Macquarie University/ ; //Macquarie University HDR Fund, Macquarie University/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; 2019-02397//Swedish Research Council/ ; },
mesh = {Humans ; Female ; Aged ; *tau Proteins/blood ; Male ; *Alzheimer Disease/blood/diagnostic imaging/psychology ; *Sphingomyelins/blood ; Cross-Sectional Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Biomarkers/blood ; Amyloid beta-Peptides/metabolism ; Cognition/physiology ; Cohort Studies ; },
abstract = {Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD triggers tau release into central and peripheral systems. Despite influence from peripheral contributions, alterations in plasma total-tau (T-tau) remain valuable in indicating AD-related neurodegeneration. Investigating relationships between SM metabolism and tau release during preclinical AD may uncover important biochemical processes and support advancing early non-invasive detection and treatment approaches. This cross-sectional study investigated cognitively unimpaired (CU) older adults from the KARVIAH cohort, grouped by cortical amyloid-β (Aβ) status through positron emission tomography (PET) imaging (CU Aβ- and CU Aβ+) and utilised a Biocrates-targeted metabolomic platform and Single-molecule array (Simoa) technology to quantify plasma levels of SMs and T-tau, respectively. Associations between circulating SMs and T-tau were examined within each group, with T-tau-associated SMs further evaluated for their association with cognitive performance and cortical Aβ burden and their potential to discriminate CU Aβ+ from CU Aβ- individuals. Significant positive correlations were observed between SMs and T-tau levels exclusively in CU Aβ+ individuals, suggesting connections between SM-mediated biochemical pathways and tau release from early neurodegeneration in preclinical AD. Lower SM levels were associated with weaker working memory and executive function, as well as poorer global cognition, indicating their potential predictive value for weaker cognitive performance. Moreover, SMs were also inversely associated with cortical Aβ load in CU Aβ+ individuals, possibly reflecting early SM-mediated neuroprotective responses against AD pathogenesis. Receiver operating characteristic analysis further revealed the significant potential of the SM panel in distinguishing cortical PET-Aβ status and enhancing the predictive performance of plasma T-tau in CU individuals. Therefore, circulating T-tau-associated SMs may serve as promising early biomarkers of lipid-mediated processes in CU older adults with cortical amyloid pathology and tau-related neurodegeneration.},
}

Humans
Female
Aged
*tau Proteins/blood
Male
*Alzheimer Disease/blood/diagnostic imaging/psychology
*Sphingomyelins/blood
Cross-Sectional Studies
Positron-Emission Tomography
Aged, 80 and over
Biomarkers/blood
Amyloid beta-Peptides/metabolism
Cognition/physiology
Cohort Studies

@article {pmid42105317,
year = {2026},
author = {Balwant Patil, K and Sugunan, S and Padiyar, A and Mishra, AK and Jain, S},
title = {Neuroprotective role of phenolic acids: mechanistic insights into cognitive decline and neurodegenerative disorder.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/1028415X.2026.2669234},
pmid = {42105317},
issn = {1476-8305},
abstract = {BACKGROUND: Age-associated cognitive deterioration and neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD), are predominantly influenced by oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation. Dietary phenolic acids, prevalent in plant-based foods, have demonstrated potential neuroprotective and cognitive-enhancing effects in recent studies.

PURPOSE: This review seeks to thoroughly assess the neuroprotective mechanisms of phenolic acids and to consolidate existing evidence from human and preclinical studies concerning their potential efficacy in alleviating cognitive impairment and neurodegeneration.

STUDY DESIGN: Narrative and evidence-based literature review.

METHODS: Recent experimental, clinical, and epidemiological studies examining significant phenolic acids - such as caffeic, chlorogenic, ferulic, gallic, rosmarinic, sinapic, ellagic, protocatechuic, p-coumaric, and tannic acids - in relation to AD, PD, and cognitive functions were retrieved from electronic databases. We put together the most important information about molecular mechanisms and treatment.

RESULTS: Preclinical studies show that phenolic acids have antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation effects by changing important signaling pathways like Nrf2/HO-1, NF-κB, and PI3 K/Akt. These actions protect dopaminergic neurons, lower the toxicity of amyloid-beta and α-synuclein, and make behavior better in disease models. Human studies suggest that increased dietary consumption of phenolic acids, especially hydroxycinnamic acids such as caffeic and chlorogenic acid, is associated with enhanced cognitive performance and a diminished risk of cognitive decline, although results are not uniform.

CONCLUSION: Phenolic acids are secure, readily accessible neuroprotective compounds that can alter various pathological pathways associated with cognitive decline and the progression of neurodegenerative diseases.},
}

@article {pmid42105452,
year = {2026},
author = {Uehara, MA and Bretecher, CA and Teschuk, JM and Verot, A and Saha, C and Fitzgerald, PB and Koski, L and Millikin, C and Moussavi, Z},
title = {Examining adverse effects in a large clinical trial of rTMS application as a treatment for Alzheimer's disease.},
journal = {Psychiatry research},
volume = {362},
number = {},
pages = {117212},
doi = {10.1016/j.psychres.2026.117212},
pmid = {42105452},
issn = {1872-7123},
abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has several advantages compared to other interventions for neurological and psychological disorders. However, various adverse effects have been reported in rTMS research, and little is known about who is most susceptible to rTMS adverse effects, or how they can be minimized.

AIMS: We aimed to identify risk factors for adverse effects reported in a recent clinical trial examining rTMS as a treatment for Alzheimer's disease (AD). We hypothesized that higher stimulation intensity would be associated with experiencing unspecified pain/discomfort, dental pain, headache, jaw pain, and muscle contractions, but not be associated with other adverse effects.

METHODS: Using detailed notes from treatment sessions, 10 adverse effects were identified. Spearman correlations were conducted to assess relationships between the highest applied stimulation intensity and normalized frequency of each adverse effect amongst those who experienced that adverse effect. Demographic information, cognitive scores, and withdrawal status were compared between the binarized groups of participants who experienced adverse effects versus those who did not. Spearman correlations were also conducted on the binarized adverse effects and the highest applied stimulation intensity. Logistic regressions were conducted to identify potential risk factors.

RESULTS: In both the sham and active treatment groups, unspecified pain/discomfort was the most common adverse effect, followed by muscle contractions and dizziness. In both the active and sham treatment groups, stimulation intensity was positively associated with muscle contractions, but was not significantly related to any other adverse effect. In evaluating groups with/without adverse effects, we found there was a significantly higher proportion of males reporting adverse effects in both the active treatment group and the sham treatment group compared to females.

CONCLUSION: The findings of this study are a step toward understanding how researchers can minimize such adverse effects, and thereby, create a less aversive experience for rTMS participants.},
}

@article {pmid42105933,
year = {2026},
author = {Pourzal, R and Agarwal, P and Leurgans, SE and McCarthy, SM and Hall, DJ and McDevitt, CA and Ganio, K and Ayton, S and Bush, AI and Grodstein, F and James, B and Agrawal, S and Hallab, NJ and Bennett, DA and Schneider, JA and Jacobs, JJ},
title = {Cobalt and titanium levels in the brain are associated with Alzheimer's disease pathology but not cognition: A study of older adults with and without total joint replacement.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.05.006},
pmid = {42105933},
issn = {1878-7568},
abstract = {Alzheimer's disease (AD) and total joint arthroplasty are prevalent and often concomitant in older adults, but an etiologic link is debated. Since wear particles are an inevitable side product of total joint arthroplasty (TJA), we hypothesized that older adults with TJA agglomerate higher-than-normal concentrations of implant alloy elements caused by the dissemination of debris from the implants, resulting in a pathological reaction. A cross-sectional analysis was conducted among 701 autopsied participants of an ongoing longitudinal cohort (Memory and Aging Project (MAP)) of whom postmortem neuropathologic data was available and implant-related metals (cobalt, titanium) were quantified in four brain regions by inductively coupled mass-spectrometry. MAP participants are enrolled without known dementia at baseline and followed annually for cognitive assessments using 19-test battery. In the analytical sample, 229 had TJA (total hip arthroplasty, total knee arthroplasty, and total shoulder arthroplasty) and n=472 had no total joint. Due to a higher likelihood of cobalt release in total hip arthroplasty, the TJA group was subdivided into a hip (n=146) and a knee/shoulder (n=83) group. We used regression and linear mixed-effects models, adjusted for demographics and apolipoprotein E ε4 status, to examine associations between metals, AD pathology and cognitive decline. Cobalt content of brain tissue was 8.9% higher in the total hip arthroplasty group than in the no-TJA group (p=0.003). Cobalt-containing particles were identified within brain tissue using scanning electron microscopy. In the inferior temporal cortex, cobalt was positively associated (p=0.0004) and titanium was negatively associated (p=0.038) with amyloid-beta load, but had no association with cognition. These results warrant monitoring the potential impact of metal implant debris on brain health. STATEMENT OF SIGNIFICANCE: This study is of great clinical significance because Alzheimer's disease (AD) and total joint arthroplasty (TJA)-the end-stage treatment of osteoarthritis-affect large and overlapping groups in our aging population. There is limited knowledge about the relationship between the prominent TJA implant metals cobalt and titanium and the pathogenesis of AD. This study shows that Co28Cr6Mo and Ti6Al4V implant alloy particles-most likely from a subset of total hip replacements with accelerated wear or tribocorrosion-can disseminate to the brain and be associated with increased cobalt and titanium concentrations. Cobalt was associated with greater AD pathology in the inferior-temporal cortex, even after correction for other known AD risk factors. However, there was no correlation with cognitive decline. Titanium was negatively associated with AD pathology, but titanium oxide appeared to be abundant in the brain from sources other than joint replacements.},
}

@article {pmid41906135,
year = {2026},
author = {Yang, R and He, Y and Pan, Y and Geng, A and Huang, F and Guo, K and Zhang, H},
title = {Multiparity exacerbates Aβ accumulation and promotes cellular senescence in a mouse model of amyloidosis.},
journal = {Immunity & ageing : I & A},
volume = {23},
number = {1},
pages = {},
pmid = {41906135},
issn = {1742-4933},
support = {82271472//the National Natural Science Foundation of China grants/ ; },
abstract = {BACKGROUND: Women have nearly twice the lifetime risk of Alzheimer’s disease (AD) as men. Hormonal and reproductive factors have been implicated; however, the role of parity, a female-specific experience, remains unknown. While epidemiological data suggest that high parity may increase the risk of dementia, the underlying biological mechanisms are unclear.

METHODS: We investigated the impact of multiparity on AD pathology using 2-month-old female 5xFAD mice. Mice were assigned to a nulliparous (0x) or multiparous (4x) (four consecutive gestation cycles) group. Brain tissues were analyzed at 6.4 months of age for Aβ pathology, neuroinflammation, synaptic markers, and senescence. Proteomic profiling and in vitro hormone treatment identified the key mediators. The role of voluntary running was assessed in a separate cohort of nulliparous mice.

RESULTS: Multiparous 5xFAD mice showed increased Aβ plaque burden, elevated BACE1 expression, synaptic loss, and activated senescence pathways compared to nulliparous controls. Proteomic analysis revealed sustained upregulation of the transcription factor FOSB. FOSB was found to drive BACE1 expression and Aβ production. In vitro co-treatment with estradiol and progesterone increased FOSB and BACE1 levels, supporting the presence of a hormone-responsive regulatory link. In nulliparous female 5xFAD mice, voluntary running from 2 to 6 months of age reduced Aβ deposition, fewer FOSB[+] neurons, and microglial activation compared with those in the sedentary controls.

CONCLUSIONS: Our findings identified the FOSB/BACE1 signaling axis as a link between reproductive history and AD pathology. Multiparity accelerates amyloid pathology and brain aging in female 5xFAD mice, mechanistically linked to hormone-driven FOSB upregulation. Physical activity downregulates this pathway in nulliparous animals. Whether exercise can mitigate parity-associated pathology remains to be investigated in multiparous animal models.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12979-026-00565-9.},
}

@article {pmid41913175,
year = {2026},
author = {Ito, K and Tsuda, S and Wake, T and Hatakeyama, A and Ogisawa, F and Ono, M and Nakayama, R and Wakui, T and Nagano, N and Iwata, A},
title = {Reframing dementia care in the era of disease-modifying therapies: informational, psychosocial, and systemic insights from Japan.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {41913175},
issn = {1472-6963},
support = {25K14240//Grants-in-Aid for Scientific Research/ ; 25GB0301//Health and Labor Sciences Research Grant/ ; },
abstract = {BACKGROUND: The introduction of disease-modifying therapies (DMTs) for Alzheimer’s disease has prompted major changes in diagnostic pathways, referral processes, and service coordination in dementia care. Japan, as an early adopter of DMTs within a nationally coordinated dementia-care framework, offers an opportunity to examine how health service structures respond to these changes. This study explored health service–related support needs emerging across the DMT pathway, focusing on patient and informal caregiver experiences, with complementary perspectives from service providers.

METHODS: A qualitative study was conducted using semi-structured interviews with 48 participants, including nine patients who underwent DMT eligibility assessment, seven informal caregivers, 11 physicians, four nurses, five clinical psychologists, five social workers, and seven community-based dementia support providers. Data were analyzed using the Framework Method, an applied qualitative approach suitable for health services research. Patients’ and caregivers’ accounts were treated as the primary analytic focus, while provider perspectives were used to contextualize system-level factors influencing care delivery.

RESULTS: Three interrelated themes were identified. First, informational support needs reflected inequitable access to trustworthy information, difficulties in sustaining understanding of complex medical explanations, and a lack of structured opportunities to revisit information over time, particularly during transitions such as ineligibility, treatment discontinuation, or completion. Second, psychosocial support needs were closely shaped by service processes, including stigma-related experiences across clinical and social contexts, family-related tensions around treatment decisions, fluctuating expectations regarding treatment effects, and limited support for adjustment when DMT was no longer an option. Third, systemic and collaborative support needs highlighted fragmented roles between primary care and DMT-designated institutions, unclear referral and handover pathways, insufficient psychosocial care capacity, and weak integration between DMT delivery systems and existing dementia-care services.

CONCLUSIONS: The implementation of DMTs has amplified pre-existing gaps in dementia care systems, revealing previously underrecognized structural vulnerabilities across informational, psychosocial, and systemic domains. Findings indicate that DMTs should be embedded within coordinated care pathways that ensure continuity of information provision, access to psychosocial support, and clear allocation of follow-up responsibility regardless of treatment eligibility. Aligning pharmacological innovation with health service design is essential to support equitable, continuous, and person-centered dementia care.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12913-026-14472-8.},
}

@article {pmid42100730,
year = {2026},
author = {Copeland, EN and Marais, AAT and Mohammad, A and Marcella, BM and Baranowski, RW and Beaudette, SM and MacPherson, REK and Fajardo, VA},
title = {Tideglusib improves novel object recognition memory in the preclinical DBA/2J mdx mouse model of Duchenne muscular dystrophy.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1812975},
pmid = {42100730},
issn = {1662-4548},
abstract = {INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder characterized by progressive muscle wasting. Approximately 1 in 3 DMD patients experience cognitive dysfunction, with research suggesting an Alzheimer's disease (AD)-like pathology. We have previously shown that treatment with the glycogen synthase kinase 3β (GSK3) inhibitor, tideglusib, improves muscle quality, function, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. In this brief follow-up study, we report the effects of tideglusib treatment on cognitive function.

METHODS: Male D2 WT and mdx mice were purchased from Jackson Laboratories. Mice were separated into the following groups: (1) WT, (2) mdx-vehicle, and (3) mdx-tideglusib (10 mg/kg/day via oral gavage for 4 weeks). A novel object recognition test was performed to assess recognition memory. Hippocampus and serum samples were collected for BACE1 activity assays, amyloid beta (Aβ) ELISAs, and western blotting.

RESULTS: Compared to vehicle-treated mdx mice, tideglusib-treated mdx mice demonstrated improved recognition memory. These changes to recognition memory were accompanied by greater expression of beta-catenin, an indirect downstream marker of GSK3 inhibition. While there were no changes in BACE1 activity, tideglusib-treated mdx mice had higher concentrations of Aβ in the serum and lower protein levels of receptor of advanced glycation end products.

DISCUSSION: The results from this brief follow-up study offer preliminary support for tideglusib as a treatment for both muscle and brain impairments in mdx mice, potentially improving cognitive function through enhanced vascular Aβ clearance.},
}

@article {pmid42097410,
year = {2026},
author = {Zhu, PF and Lyu, Z and Wang, Q and Li, S and Wang, X and Luo, A},
title = {ISRIB as a Prototype eIF2B Activator: Pharmacology, Mechanisms, and Translational Potential in Aging-Related Cognitive Disorders.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108228},
doi = {10.1016/j.phrs.2026.108228},
pmid = {42097410},
issn = {1096-1186},
abstract = {Aging-related cognitive disorders have been increasingly linked to maladaptive stress pathways that persistently impair synaptic protein synthesis and plasticity. The integrated stress response (ISR) links various stressors to downstream translational reprogramming through the phosphorylation of eIF2α. Acute ISR activation can be protective, while chronic ISR activation may confine neurons and glial cells to hypo-plastic states, impairing learning and memory function. ISRIB is a prototype small molecule that activates eIF2B and restores translation homeostasis, providing a viable framework for "tuning" ISR output rather than indiscriminately blocking stress signaling. This review summarizes ISR biology in the aging brain, emphasizes cell-type heterogeneity, and evaluates the evidence for ISRIB across various conditions, including normal aging, Alzheimer's disease, vascular cognitive impairment, synucleinopathies, perioperative neurocognitive disorders, and related conditions with shared ISR pathology. We then discuss dosing, safety, optimization, limitations, translational biomarkers, and lessons from emerging clinical-stage eIF2B activators. Finally, we propose precision and combination strategies to tailor ISR modulation to disease stage, pathological context, and therapeutic window, aiming to provide new directions and a theoretical basis for the treatment of aging-related cognitive disorders.},
}

@article {pmid42097478,
year = {2026},
author = {Matošević, A and Maraković, N and Barić, D and Igert, A and Brazzolotto, X and Kovarik, Z and Bosak, A},
title = {Integrative Structural and Kinetic Analysis of the Molecular Basis for Reduced Carbamate Inhibition in Atypical Butyrylcholinesterase.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112134},
doi = {10.1016/j.cbi.2026.112134},
pmid = {42097478},
issn = {1872-7786},
abstract = {Butyrylcholinesterase (BChE) plays a key role in cholinergic transmission and the metabolism of various drugs, making its regulation a promising therapeutic strategy for several diseases, including Alzheimer's disease. Selective inhibition of BChE helps regulate brain acetylcholine levels. However, genetic polymorphisms in the BCHE gene, particularly the Asp70Gly mutation in atypical BChE, can impact treatment outcomes. This study compares the inhibitory potency of 13 carbamates against atypical and usual BChE. Using molecular docking, quantum chemical cluster calculations, and crystallization of wild-type BChE with the most potent carbamate, we identified key differences in carbamylation mechanisms. Atypical BChE shows a less favorable enzyme-inhibitor complex orientation, lacking the hydrogen bond stabilization of the reactive carbonyl oxygen. Additionally, Asp70 in usual BChE contributes to stabilizing the non-reactive carbamate group, whereas Gly70 in atypical BChE is too distant to form such interactions.},
}

@article {pmid42097853,
year = {2026},
author = {Rohatgi, S and Omid-Fard, N and Zhu, S and Martinez Imbett, RE and Ford, JN and Dowling, TP and Kirsch, JE and Romero, JM},
title = {Relationship of Inferior Frontal Sulcal Hyperintensities with Amyloid-Related Imaging Abnormalities.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9395},
pmid = {42097853},
issn = {1936-959X},
abstract = {OBJECTIVE: Anti-amyloid immunotherapies used to treat Alzheimer's disease (AD) are often associated with amyloid-related imaging abnormalities (ARIA). We aim to indirectly assess glymphatic function by using inferior frontal sulcal hyperintensity (IFSH) as a biomarker in patients receiving anti-amyloid therapy, both with and without ARIA, as well as in healthy controls. We hypothesize that patients who develop ARIA will have higher IFSH scores than non-ARIA patients and healthy controls.

METHODS: Eligible AD patients who received anti-amyloid treatment were included in our retrospectively collected dataset. Only scans performed at 3T were used. Inter-rater reliability was evaluated and statistical analyses of IFSH scores and demographic data were performed to compare between groups. Additionally, within-subject analysis was used to compare the baseline and ARIA scans. Significance set at P < 0.05.

RESULTS: A total of 104 patients were selected based on the study criteria, of whom 60 had a clinical diagnosis of dementia. 36 patients developed ARIA, while 24 did not develop ARIA. 23 were age-matched healthy controls, and 21 were young healthy controls. Inter-rater reliability between the two readers was concordant when using quadratic weights appropriate for ordinal data (κ (w) = 0. 91, 95% CI 0.86-0.95). IFSH was significantly higher in the older age cohorts compared to young healthy controls (median 3.5 [IQR 2.5-5] versus 0 [0-1], P<0.001), with no significant difference between the dementia and healthy elderly groups (3.25 [3-4.875] versus 3.5 [2.5-5]). Among dementia patients on anti-amyloid therapy, significantly higher IFSH was observed in ARIA patients (at time of ARIA scan) compared to their non-ARIA counterparts (3.75 [3-5] versus 3 [2-4], P= 0.04). There was no significant difference in IFSH score between baseline and ARIA scans (P = 0.16).

CONCLUSION: IFSH was higher among dementia patients on anti-amyloid therapy with ARIA than among their non-ARIA counterparts. This supports its role as a potential biomarker of glymphatic dysfunction, although its utility on an individual basis is limited. Future prospective studies could benefit from incorporating IFSH as a variable, particularly if glymphatic therapies become a reality.},
}

@article {pmid42098313,
year = {2026},
author = {Shinagawa, S and Onuki, K and Shimizu, K},
title = {Physicians' perceptions and treatment practices for agitation associated with Alzheimer's dementia vary by specialty in Japan.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-51118-5},
pmid = {42098313},
issn = {2045-2322},
support = {NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; },
abstract = {Agitation, a behavioural and psychological symptom of dementia, is under-recognized in Japan. To describe the physician's perceptions and treatment practice for agitation in Alzheimer's dementia (AAD) in Japan, we conducted a cross-sectional web-based survey in October 2024. The survey included physicians in neurology, neurosurgery, psychiatry, or general internal medicine who were registered with the survey panel; consented to participation; affiliated with hospitals or clinics; treating ≥ 10 people with Alzheimer's dementia (AD)/month. Responses from 529 physicians showed that they treated an average of 35.0 people with AD per month, of whom 8.4 (24%) had AAD. When asked what "agitation" brought to mind, physicians most commonly selected the Japanese term for "excitability", corresponding to the "agitation/aggression" item in the Neuropsychiatric Inventory (58.6%). In general internal medicine, 24.2% were unaware of agitation. Anti-dementia drugs (91.7%) were most frequently selected as new medications for AD, whereas in psychiatry, antipsychotics were most frequently selected (95.8%), and side effects were cited more often as a key consideration than in other specialties. These results suggest that perceptions and treatment practices vary by specialty, particularly reflected in common antipsychotic prescriptions with higher safety awareness among psychiatrists and limited recognition of AAD in others, especially in general internal medicine.},
}

@article {pmid42098771,
year = {2026},
author = {Badot, C and Bini, A and Duplan, E and Checler, F and Lauritzen, I},
title = {Functional relationships linking C99/APP-βCTF dimerization, proteostasis disruption, and organelle dysfunction.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02928-7},
pmid = {42098771},
issn = {1478-811X},
abstract = {BACKGROUND: The amyloid β (Aβ) precursor C99 (or APP-βCTF) accumulates in Alzheimer's disease and has been proposed to display Aβ-independent toxicity, notably by affecting the endosomal-lysosomal-autophagic (ELA) network. Our previous findings suggested that some ELA-associated C99 could correspond to dimeric and oligomeric species, but the intracellular sites of C99 dimerization, as well as the toxicity linked to it, remains unknown.

METHODS: We here developed a bimolecular fluorescence complementation (BiFC) probe to visualize de novo C99 dimerization and dimer trafficking, as well as to identify possible cellular responses specifically linked to C99 dimerization. Moreover, to confirm dimer localizations and toxicities, the localization and cellular effects of the dimerization mutant C99[G29L/G33L] was compared to that of wildtype C99. The C99 constructs were transfected into HeLa cells and dimer localizations, expression levels and intracellular toxicities were evaluated by Western blot and immunocytochemistry.

RESULTS: BiFC-C99 dimers were first detected within the TGN, in which monomers initially accumulate. The proteasomal inhibitor MG-132 led to increased dimer formation, indicating that the proteasomal activity status is a key determinant of C99 dimerization. Conversely, TGN-associated C99 dimerization had a negative impact on both the ubiquitin-proteasome system (UPS) and the TGN, as highlighted by the appearance of p62/SQSTM1-positive aggresomes and fragmented Golgi, then suggesting a two-way relationship between UPS function and C99 dimerization. Dimerization also led to lysosome repositioning and to the accumulation of LC3B-positive autophagy vesicles, agreeing with the well-known interplay between autophagy and proteasome in protein turnover. P62/SQSTM1 and LC3B accumulation could similarly be observed in cells expressing C99[G29L/G33L], a mutant favoring dimerization, while this was not the case in wildtype C99 expressing cells, confirming the dimerization-specific effect. While proteasomal inhibition caused TGN-associated dimer formation, repression of γ-secretase-mediated C99 proteolysis instead led to a redistribution of monomers to EEA1-positive endosomes, whereas already existing C99 dimers remained unaffected by this treatment. These new endosome-associated monomers were found also to dimerize, resulting in dimers destined for either secretion via small extracellular vesicles or autophagy-lysosomal degradation.

CONCLUSIONS: Taken together, our findings indicate that the cellular status of UPS, autophagy and γ-secretase activities are all determinant for C99 expression levels, and are thus crucial for both the level of C99 dimerization and for the fate of the dimers. Moreover, our data show that C99 dimerization itself negatively affects these activities thereby indicating a two-way relationship between C99 dimerization, proteostasis disruption and organelle dysfunction.},
}